2-pyridyl substituted imidazoles as ALK5 and/or ALK4 inhibitors

ABSTRACT

2-pyridyl substituted imidazoles of the formula (I) as shown in claim  1 , are provided, which are useful in the treatment of diseases mediated by ALK5 or ALK4 inhibitors or both.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part (CIP) of U.S. applicationSer. No. 12/155,984, filed on Jun. 12, 2008, which is a CIP of U.S.application Ser. No. 10/983,227, filed on Nov. 8, 2004, which claimspriority to Korean Application No. 10-2004-0027591, filed on Apr. 21,2004. These applications are incorporated fully herein by reference.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

This invention relates to 2-pyridyl substituted imidazoles which areinhibitors of the transforming growth factor-β (TGF-β) type I receptor(ALK5) and/or the activin type I receptor (ALK4), methods for theirpreparation, and their use in medicine, specifically in the treatmentand prevention of a disease state mediated by these receptors.

2. Background of the Invention

TGF-β denotes a family of proteins, TGF-β1, TGF-β2 and TGF-β3, which arepleiotropic modulators of cell proliferation and differentiation, woundhealing, extracellular matrix production and immunosuppression. Othermembers of this superfamily include activins, inhibins, bonemorphogenetic proteins, growth and differentiation factors and Müllerianinhibiting substance.

TGF-β1 transduces signals through two highly conserved singletransmembrane serine/threonine kinases, the type I (ALK5) and type IITGF-β receptors. Upon ligand induced oligomerization, the type IIreceptor hyperphosphorylates serine/threonine residues in the GS regionof the ALK5, which leads to activation of the ALK5 by creating a bindingsite for Smad proteins. The activated ALK5 in turn phosphorylates Smad2and Smad3 proteins at the C-terminal SSXS-motif thereby causing theirdissociation from the receptor and heteromeric complex formation withSmad4. Smad complexes translocate to the nucleus, assemble with specificDNA-binding co-factors and co-modulators to finally activatetranscription of extracellular matrix components and inhibitors ofmatrix-degrading proteases.

Activins transduce signals in a manner similar to TGF-β. Activins bindto serine/thereonine kinase, the activin type II receptor (ActRIIB), andthe activated type II receptor hyperphosphorylates serine/threonineresidues in the GS region of the ALK4. The activated ALK4 in turnphosphorylates Smad2 and Smad3. The consequent formation of ahetero-Smad complex with Smad4 results in the activin-induced regulationof gene transcription.

Numerous experimental animal studies demonstrate an association betweenglomerular expression of TGF-β and fibrosis, including the Thy-1 ratmodel of proliferative glomerulonephritis, anti-GBM glomerulonephritisin rabbits, and the ⅚ nephrectomy rat model of focal segmentalglomerulosclerosis, as has been reviewed recently (e.g., Bitzer, M. etal., Kidney Blood Press. Res. 21:1-12 (1998)). Neutralizing antibody toTGF-β improves glomerular histology in the Thy-1 nephritis model (e.g.,Border, W. A. et al., Nature 346: 371-374 (1990)).

Hyperglycemic conditions increase TGF-β mRNA and protein synthesis inboth murine proximal tubule cells and human mesangial cells (e.g.,Wahab, N. A. et al., Biochem. J. 316:985-992 (1996); Rocco, M. V. etal., Kidney Int. 41: 107-114 (1992)). Diabetic patients with earlykidney disease show increased accumulation of TGF-β mRNA and proteinwithin the glomerulus (e.g., Yoshioka, K. et al., Lab. Invest. 68:154-163 (1993)). In kidneys with chronic renal interstitial fibrosis,the hallmarks are thickened tubular basement membranes and an expandedinterstitial compartment, with interstitial fibrosis characterized by anincrease in collagens I, III, V, VII, and fibronectin (e.g., Eddy, A.A., J. Am. Soc. Nephrol. 7: 2495-2508 (1996)).

TGF-β gene expression and protein production are increased in a varietyof animal models of pulmonary fibrosis including bleomycin, silica,asbestos, and radiation (e.g., Phan, S. H. and Kunkel, S. L., Exp. LungRes. 18: 29-43 (1992); Williams, A. O. et al., Am. J. Pathol. 142:1831-1840 (1993); Rube, C. E. et al., Int. J. Radiat. Oncol. Biol. Phys.47: 1033-1042 (2000)). Coincident increase in TGF-β1 protein andcollagen gene expression in adjacent tissue slices from idiopathicpulmonary fibrosis is observed in human pulmonary fibrotic disease(e.g., Broekelmann, T. J. et al., Proc. Natl. Acad. Sci. USA88:6642-6646 (1991)). Increased TGF-β production has been documented inpatients with sarcoidosis, pneumoconiosis, asbestosis, andradiation-induced fibrosis (e.g., Khalil, N. et al., Am. J. Respir.Cell. Mol. Biol. 14:131-138 (1996); Jagirdar, J. et al., Environ. HealthPerspect. 105:1197-1203 (1997)). Anti-TGF-β antibodies and TGF-β-solublereceptors could partially inhibit fibrosis in bleomycin-induced lungfibrosis rodent models (e.g., Giri, S. N. et al., Thorax 48: 959-966(1993); Wang, Q. et al., Thorax 54: 805-812 (1999)). Tobacco smoke hasbeen implicated as one of the most important factors that can causesmall airway disease followed by chronic obstructive pulmonary disease(COPD) (e.g., Wright, J. M. et al., Am. Rev. Respir. Dis. 146: 240-262(1992)). COPD is a slowly progressive and irreversible disordercharacterized by the functional abnormality of airway obstruction. TGF-βhas been hypothesized to be involved in airway remodeling found inchronic airway inflammatory disorders such as COPD (e.g., Takizawa, H.Int. J. Mol. Med. 1: 367-378 (1998); Ning, W. et al., Proc. Natl. Acad.Sci. USA 101:14895-14900 (2004)).

Hepatic stellate cells (HSC) are the major source of extracellularmatrix proteins in hepatic fibrosis. Extracellular matrix production byactivated hepatic stellate cells is markedly increased through theaction of TGF-β1 (e.g., Friedman, S. L., Prog. Liver Dis. 14: 101-130(1996); Pietrangelo, A., Semin. Liver Dis. 16:13-30 (1996)). Transgenicmice that overexpress TGF-β1 in the liver develop hepatic fibrosis aswell as extrahepatic pathologies such as renal fibrosis (e.g.,Sanderson, N. et al., Proc. Natl. Acad. Sci. USA 92:2572-2576 (1995)).

TGF-β1 and its receptors are overexpressed in injured blood vessels andin fibroproliferative vascular lesions leading to overproduction ofextracellular matrix (e.g., Saltis, J. et al., Clin. Exp. Pharmacol.Physiol. 23: 193-200 (1996); McCaffrey, T. A. et al., J. Clin. Invest.96: 2667-2675 (1995)).

Anti-TGF-β antibodies reduce scar formation and improve thecytoarchitecture of the neodermis in rats (e.g., Shah, M., J. Cell. Sci.108: 985-1002 (1995)), improve healing of corneal wounds in rabbits(e.g., Moller-Pedersen, T., Curr. Eye Res. 17:736-747 (1998)), andaccelerate wound healing of gastric ulcers in rats (e.g., Ernst, H., Gut39: 172-175 (1996)).

Radiation fibrosis is a frequent sequel of therapeutic or accidentalradiation overexposure in normal human tissues. TGF-β1 plays a centralrole in the initiation, development, and persistence of radiationfibrosis, as has been reviewed recently (e.g., Martin, M. et al., Int.J. Radiat. Oncol. Biol. Phys. 47:277-290 (2000)).

Organ transplantation is complicated in many instances by chronicrejection and for some organs such as the kidney, it is the major formsof graft loss. In human patients, chronic rejection of lung and kidneytransplants is associated with increased expression of TGF-β within thetissue (e.g., El-Gamel, A. et al., Eur J. Cardiothorac. Surg. 13:424-430 (1998); Shihab, F. S. et al., J. Am. Soc. Nephrol. 6:286-294(1995)).

TGF-β is implicated in peritoneal adhesions (e.g., Saed, G. M. et al.,Wound Repair Regeneration 7: 504-510 (1999)). The peritoneal andsub-dermal fibrotic adhesions could be prevented by inhibitors of ALK5and/or ALK4.

The tumor cells and the stromal cells within the tumors in late stagesof various cancers generally overexpress TGF-β. This leads tostimulation of angiogenesis and cell motility, suppression of the immunesystem, and increased interaction of tumor cells with the extracellularmatrix (e.g., Hojo, M. et al., Nature 397: 530-534 (1999)).Consequently, the tumor cells become more invasive and metastasize todistant organs (e.g., Maehara, Y. et al., J. Clin. Oncol. 17: 607-614(1999); Picon, A. et al., Cancer Epidemiol. Biomarkers Prev. 7:497-504(1998)).

Plasminogen activator inhibitor-1 (PAI-1) is the major physiologicalinhibitor of both tissue-type plasminogen activator and urokinase-typeplasminogen activator. Elevated levels of PAI-1 are associated withthrombosis and vascular disease, suggesting that high plasma PAI-1 maypromote a hypercoagulable state by disrupting the natural balancebetween fibrinolysis and coagulation (e.g., Vaughan, D. E., J. Invest.Med. 46: 370-376 (1998)). It is known that TGF-β stimulates theexpression of PAI-1 (e.g., Dennler, S. et al., EMBO J. 17: 3091-3100(1998)). Accordingly, inhibition of the production of PAI-1 with aninhibitor of the TGF-β signaling pathway could produce a novelfibrinolytic therapy.

Activin signaling and overexpression of activin is linked topathological disorders that involve extracellular matrix accumulationand fibrosis (e.g., Matsuse, T. et al., Am. J. Respir Cell MoL Biol.13:17-24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm.205:441-48 (1994); Matsuse, T. et al., Am. J. Pathol. 148:707-713(1996); De Bleser et al., Hepatology 26:905-912 (1997); Pawlowski, J.E., et al., J. Clin. Invest. 100:639648 (1997); Sugiyama, M. et al.,Gastroenterology 114:550-558 (1998); Munz, B. et al., EMBO J.18:5205-5215 (1999)), inflammatory responses (e.g., Rosendahl, A. etal., Am. J. Respir Cell Mol. Biol. 25:60-68 (2001), cachexia or wasting(Matzuk, M. M. et al., Proc. Natl. Acd. Sci. USA 91:8817-8821 (1994);Coerver, K. A. et al., Mol. Endocrinol. 10:534-543 (1996); Cipriano, S.C. et al., Endocrinology 141:2319-2327 (2000)), diseases or pathologicalresponses in the central nervous system (e.g., Logan, A. et al., Eur J.Neurosci. 11:2367-2374 (1999); Logan, A. et al., Exp. Neurol.159:504-510 (1999); Masliah, E. et al., Neurochem. Int. 39:393-400(2001); De Groot, C. J. A. et al., J. Neuropathol. Exp. Neurol.58:174-187 (1999); John, G. R. et al., Nat. Med. 8:1115-1121 (2002)) andhypertension (e.g., Dahly, A. J. et al., Am. J. Physiol. Regul. Integr.Comp. Physiol. 283: R757-767 (2002)). Studies have shown that TGF-β andactivin can act synergistically to induce extracellular matrixproduction (e.g., Sugiyama, M. et al., Gastroenterology 114; 550-558(1998)).

Therefore, it becomes evident that inhibition of ALK5 and/or ALK4phosphorylation of Smad2 and Smad3 by the preferred compounds of thisinvention could treat and prevent disorders involving these signalingpathways.

WO 00/61576 and US 2003/0149277 A1 disclose triarylimidazole derivativesand their use as ALK5 inhibitors. WO 01/62756 A1 disclosespyridinylimidazole derivatives and their use as ALK5 inhibitors. WO02/055077 A1 discloses use of imidazolyl cyclic acetal derivatives asALK5 inhibitors. And, also, WO 03/087304 A2 discloses tri-substitutedheteroaryls and their use as ALK5 and/or ALK4 inhibitors.

SUMMARY OF THE INVENTION

Surprisingly, it has now been discovered that a class of 2-pyridylsubstituted imidazoles function as potent and selective inhibitors ofALK5 and/or ALK4 and therefore, have utility in the treatment andprevention of various disease states mediated by ALK5 and/or ALK4, suchas glomerulonephritis, diabetic nephropathy, lupus nephritis,hypertension-induced nephropathy, renal interstitial fibrosis, renalfibrosis resulting from complications of drug exposure, HIV-associatednephropathy, transplant necropathy, liver fibrosis due to alletiologies, hepatic dysfunction attributable to infections,alcohol-induced hepatitis, disorders of the biliary tree, pulmonaryfibrosis, acute lung injury, adult respiratory distress syndrome,idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease,pulmonary disease due to infectious or toxic agents, post-infarctioncardiac fibrosis, congestive heart failure, dilated cardiomyopathy,myocarditis, vascular stenosis, restenosis, atherosclerosis, ocularscarring, corneal scarring, proliferative vitreoretinopathy, excessiveor hypertrophic scar or keloid formation in the dermis occurring duringwound healing resulting from trauma or surgical wounds, peritoneal andsub-dermal adhesion, scleroderma, fibrosclerosis, progressive systemicsclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis,ulcers, impaired neurological function, male erectile dysfunction,Peyronie's disease, Dupuytren's contracture, Alzheimer's disease,Raynaud's syndrome, fibrotic cancers, tumor metastasis growth,radiation-induced fibrosis, and thrombosis.

BRIEF DESCRIPTION OF THE DRAWINGS

The aforementioned aspects and other features of the present inventionwill be explained in the following description, taken in conjunctionwith the accompanying drawings, wherein:

FIG. 1 shows effect of the compounds of Examples 32, 45, 73, 79, and 83on TGF-β1-induced 3TP-Luc reporter activity in HepG2 cells.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In an embodiment of the present invention, there is provided a compoundof formula (I) or a pharmaceutically acceptable salt thereof:

wherein R₁ is naphthyl, anthracenyl, or phenyl optionally substitutedwith substituents selected from halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,C₁₋₆alkyl, C₁₋₆haloalkyl, —O—(CH₂)_(n)-Ph, —S—(CH₂)_(n)-Ph, cyano,phenyl, and CO₂R, wherein R is H or C₁₋₆alkyl, and n is 0, 1, 2, or 3;or R₁ is phenyl or pyridyl fused with an aromatic or non-aromatic cyclicring of 5-7 members wherein said cyclic ring optionally contains up tothree heteroatoms, independently selected from N, O and S, and the fusedphenyl or pyridyl may be further optionally substituted by halo, OH,—O—C₁₋₆alkyl, —S—C₁₋₆ alkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, cyano, phenyl or═O; is H, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl, phenyl,C₁₋₆haloalkyl, NH₂, NH(CH₂)_(n)-Ph, NH—C₁₋₆alkyl, halo, CN, NO₂, CONHRor SO₂NHR, wherein R is H or C₁₋₆alkyl, and ni s 0, 1, 2, or 3;

R₃ is

or R₃ heteroaromatic cyclic ring optionally substituted withsubstituents selected from halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,C₁₋₆alkyl, C₁₋₆haloalkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,—O—(CH₂)_(n)-Ph, —S—(CH₂)_(n)-Ph, cyano, phenyl, and CO₂R, wherein R isH or C₁₋₆alkyl, and n is 0, 1, 2, or 3; or R₃ is phenyl fused with anaromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclicring optionally contains up to three heteroatoms, independently selectedfrom N, O and S, and the fused phenyl may be further optionallysubstituted by halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl,C₁₋₆haloalkyl, cyano, or phenyl;

R₄ is halo, C₁₋₆haloalkyl, —SO₂C₁₋₆alkyl or non-aromatic cyclic ring of5-7 members wherein said cyclic ring optionally contains up to threeheteroatoms, independently selected from N, O and S;

R₅ and R₆ are independently H, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,—(CH₂)_(p)—NO₂, —(CH₂)_(p)—NR₇R₈, —(CH₂)_(p)—CHO, —(CH₂)_(p)—CONHOH,—(CH₂)_(p)—CN, —(CH₂)_(p)—CO₂H, —(CH₂)_(p)—CO₂R₇, —(CH₂)_(p)—CONR₇R₈,—(CH₂)_(p)—C(═NR₇)NR₇R₈, —(CH₂)_(p)-tetrazole, —(CH₂)_(p)—COR₇,—(CH₂)_(q)—(OR₉)₂, —(CH₂)_(p)—OR₇, —(CH₂)_(p)—CH═CH—CN,—(CH₂)_(p)—CH═CH—CO₂H, —(CH₂)_(p)—CH═CH—CO₂R₇, —(CH₂)_(p)—CH═CH—CONR₇R₈,—(CH₂)_(p)—NHCOR₇, —(CH₂)_(p)—NHCO₂R₇, —(CH₂)_(p)—CONHSO₂R₇,—(CH₂)_(p)—NHSO₂R₇ or —(CH₂)_(p)—CH═CH-tetrazole;

R₇ and R₈ are independently H, phenyl or C₁₋₆alkyl wherein phenyl orC₁₋₆alkyl is optionally substituted by —(CH₂)_(q)—CONHOH, —(CH₂)_(q)—CN,—(CH₂)_(q)—CO₂R₁₀, —(CH₂)_(q)—CONR₁₁R₁₂, —(CH₂)_(q)-tetrazole,—(CH₂)_(r)—OR₁₀, —(CH₂)_(r)—R₁₃, —(CH₂)_(r)—NR₁₁R₁₂; or R₇ and R₈ aretaken together to form non-aromatic cyclic ring of 3-6 members whereinsaid cyclic ring optionally contains up to three heteroatoms,independently selected from N, O and S;

R₉ is C₁₋₆alkyl;

R₁₀, R₁₁ and R₁₂ are independently H or C₁₋₆alkyl;

R₁₃ is 3-7 membered heterocyclic ring optionally substituted at one, twoor three positions by halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl,C₁₋₆haloalkyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, cyano, oxo,carboxy or nitro;

p is 0, 1, 2, 3, or 4;

q is 1, 2, 3, or 4;

r is 2, 3, or 4;

X is C₁₋₁₀alkylene, C₂₋₁₀alkenylene or C₂₋₁₀alkynylene;

one of A₁ and A₂ is N and the other is NR₁₄; and

R₁₄ is H, OH, C₁₋₆alkyl, or C₃₋₇cycloalkyl.

As used herein, the double bond indicated by the dotted lines of formula(I), represent the possible tautomeric ring forms of the compoundsfalling within the scope of this invention, the double bond being to theunsubstituted nitrogen.

Preferably, R₁ is naphthyl or phenyl optionally substituted withsubstituents selected from halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,C₁₋₆alkyl, and phenyl; or R₁ is phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to two heteroatoms, independently selected fromN, O and S, and the fused phenyl ring may be further optionallysubstituted by halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl orC₁₋₆haloalkyl. For example, R₁ represents benzo[1,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, benzoxazolyl, benzothiazolyl,benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, quinoxalin-6-yl,quinolin-6-yl, dihydrobenzofuranyl, benzimidazolyl, C₁₋₆benzimidazolyl,benzoxazolyl-2-one or benzo[1,4]oxazinyl.

Preferably, R₂ is other than H. When R₂ is other than H, it ispreferably positioned ortho to the nitrogen of the pyridyl ring. R₂ ispreferably C₁₋₄ alkyl.

Preferably, R₃ is

or R₃ is heteroaromatic cyclic ring optionally substituted withsubstituents selected from halo, OH, —O—C₁₋₃alkyl, C₁₋₃alkyl,C₁₋₃haloalkyl, amino, C₁₋₃ alkylamino, di(C₁₋₃alkyl)amino, cyano,carboxy, and CO₂R, wherein R is H or C₁₋₃alkyl; or R₃ is phenyl fusedwith an aromatic or non-aromatic cyclic ring of 5-6 members wherein saidcyclic ring optionally contains up to three heteroatoms, independentlyselected from N, O and S, and the fused phenyl may be further optionallysubstituted by halo, —O—C₁₋₃alkyl, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano.

Preferably, R₄ is halo, C₁₋₃haloalkyl, —SO₂C₁₋₆alkyl or non-aromaticcyclic ring of 5-6 members wherein said cyclic ring optionally containsup to two heteroatoms, independently selected from N and O;

Preferably, R₅ and R₆ are independently H, halo, —(CH₂)_(p)—NO₂,—(CH₂)_(p)—NR₇R₈, —(CH₂)_(p)—CN, —(CH₂)_(p)—CO₂H, —(CH₂)_(p)—CO₂R₇,—(CH₂)_(p)—CONR₇R₈, —(CH₂)_(p)—OR₇.

Preferably, R₇ and R₈ are independently H, phenyl or C₁₋₆alkyl whereinphenyl or C₁₋₆alkyl is optionally substituted by —(CH₂)_(q)—CO₂R₁₀,—(CH₂)_(q)—CONR₁₁R₁₂, —(CH₂)_(r)—OR₁₀, —(CH₂)_(r)—R₁₃,—(CH₂)_(r)—NR₁₁R₁₂, or R₇ and R₈ are to form non-aromatic cyclic ring of3-6 members wherein said cyclic ring optionally contains up to threeheteroatoms, independently selected from N, O and S;

Preferably, R₁₀, R₁₁ and R₁₂ are independently H or C₁₋₃alkyl.

Preferably, R₁₃ is 3-6 membered heterocyclic ring.

Preferably, p is 0, 1, or 2.

Preferably, q is 1, 2, or 3.

Preferably, r is 2 or 3.

Preferably, X is C₁₋₆alkylene.

Preferably, one of A₁ and A₂ is N and the other is NR₁₄, wherein R₁₄ isH.

Specific compounds of the invention which may be mentioned include thefollowing and pharmaceutically acceptable salts or hydrates thereof:

-   6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)quinoline-   2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline-   6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline-   6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline-   2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-2-methylquinoline-   6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline-   6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline-   2-(4-(4-methoxyphenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(2-(3-chlorobenzyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(4-(4-chlorophenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(4-(4-chlorophenyl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-chlorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine-   2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine-   6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-chloropyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-chlorobenzyl)-5-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-chloro-6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(2,3-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   6-(5-(6-methylpyridin-2-yl)-2-(3-phenoxybenzyl)-1H-imidazol-4-yl)quinoxaline-   6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine-   6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline-   6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-chloro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide-   6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol-   6-(2-((6-chloropyridin-3-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoline-   6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoxaline-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylethanamine-   6-(2-(4-fluoro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   4-(2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethyl)morpholine-   3-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylpropan-1-amine-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenylamino)ethanol-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol-   6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   Methyl    2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol-   6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetic    acid-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine-   methyl    2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetic    acid-   2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide-   6-(2-((6-chloropyridin-2-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoic    acid-   6-(2-(4-fluoro-3-(1H-tetrazol-5-yl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   2-fluoro-N-(2-methoxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide-   2-fluoro-N-(2-hydroxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide-   (2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanamine-   (2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanol-   6-(5-(6-methylpyridin-2-yl)-2-(3-(pyrrolidin-1-yl)benzyl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline-   2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline-   6-(5-(6-methylpyridin-2-yl)-2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-bromobenzyl)-5-(pyridin-2-yl)-1H-imidazol-4-yl)quinoline-   6-(2-(4-bromobenzyl)-5-(6-methoxypyridin-2-yl)-1H-imidazol-4-yl)quinoline;    and a pharmaceutically acceptable salt or hydrate thereof.

The compounds of the present invention typically are small organicmolecules (non-peptide small molecules), generally less than about 1,000daltons in size. Preferred non-peptide small molecules have molecularweights of less than about 750 daltons, more preferably less than about500 daltons, and even more preferably less than about 300 daltons.

Compounds of formula (I) may also be supplied in the form of a “prodrug”which is designed to release compound of formula (I) when administeredto a subject. Prodrug formed designs are well known in the art, anddepend on the substituents contained in compound of formula (I). Forexample, a substituent containing hydroxyl could be coupled to a carrierwhich renders the compound biologically inactive until it is removed byendogenous enzymes or, for example, by enzymes targeted to a particularreceptor or location in the subject.

A compound of formula (I) that is acidic in nature (e.g., having acarboxyl or phenolic hydroxyl group) can form a pharmaceuticallyacceptable salt such as a sodium, potassium, calcium, or gold salt. Alsowithin the scope of the invention are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, andN-methylglycamine. A compound of formula (I) can be treated with an acidto form acid addition salts. Examples of such acids include hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonicacid, phosphoric acid, p-bromophenylsulfonic acid, carbonic acid,succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid,salicylic acid, malic acid, fumaric acid, ascorbic acid, maleic acid,acetic acid, and other mineral and organic acids well known to thoseskilled in the art. The acid addition salts can be prepared by treatinga compound of formula (I) in its free base form with a sufficient amountof an acid (e.g., hydrochloric acid) to produce an acid addition salt(e.g., a hydrochloride salt). The acid addition salt can be convertedback to its free base form by treating the salt with a suitable diluteaqueous basic solution (e.g., sodium hydroxide, sodium bicarbonate,potassium carbonate, or ammonia).

Some of the compounds of this invention may be crystallized orrecrystallized from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilization.

Compounds of formula (I) may contain one or more asymmetric centers andthus can exist as enantiomers or diastereomers. It is to be understoodthat the invention includes both mixtures and separate individualisomers of compounds of the formula (I). Furthermore, certain compoundsof the formula (I) which contain alkenyl groups may exist as cis- ortrans-isomers. In each instance, the invention includes both mixturesand separate individual isomers.

Compounds of formula (I) may also exist in tautomeric forms and theinvention includes both mixtures and separate individual tautomersthereof.

Also included in the invention are radiolabelled derivatives ofcompounds of formula (I) which are suitable for biological studies.

As used herein, the term “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-10 (e.g., 1-6 or 1-4) carbon atoms. Analkyl group can be straight or branched. Examples of an alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and2-ethylhexyl. An alkyl group can be optionally substituted with one ormore substituents such as alkoxy, cycloalkoxy, amino, nitro, carboxy,cyano, halo, hydroxy, sulfo, or mercapto.

As used herein, the term “alkylene” group refers to a saturatedaliphatic hydrocarbon group containing 1-10 (e.g., 1-6 or 1-4) carbonatoms. An alkylene group can be straight or branched. Examples of analkylene group include, but are not limited to, methylene, ethylene,propylene, isopropylene, butylene, isobutylene, sec-butylene,tert-butylene, n-pentylene, n-heptylene, and 2-ethylhexylene. Analkylene group can be optionally substituted with one or moresubstituents such as alkoxy, cycloalkoxy, amino, nitro, carboxy, cyano,halo, hydroxy, sulfo, or mercapto.

As used herein, the term “alkenylene” group refers to an aliphaticcarbon group that contains 2-10 (e.g., 2-6 or 2-4) carbon atoms and atleast one double bond. Like an alkylene group, an alkenylene group canbe straight or branched. Examples of an alkenylene group include, butare not limited to, allylene, isoprenylene, 2-butenylene, and2-hexenylene. An alkenylene group can be optionally substituted with oneor more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy,aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro,carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl,alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino, heterocycloalkylcarbonylamino,heterocycloalkylalkylcarbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide,alkoxycarbonyl, or alkylcarbonyloxy.

As used herein, the term “alkynylene” group refers to an aliphaticcarbon group that contains 2-10 (e.g., 2-6 or 2-4) carbon atoms and hasat least one triple bond. An alkynylene group can be straight orbranched. Examples of an alkynylene group include, but are not limitedto, propargylene and butynylene. An alkynylene group can be optionallysubstituted with one or more substituents such as alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo,mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,heterocycloalkylcarbonylamino, heterocycloalkylalkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.

As used herein, the term “cycloalkyl” group refers to an aliphaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, adamantly, norbornyl, cubyl, octahydroindenyl,decahydronaphthyl; bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl.

As used herein, the term “alkoxy” group refers to an alkyl-O-group where“alkyl” has been defined previously.

As used herein, the term “haloalkyl” group refers to an alkyl groupcontaining one or more halogen atoms. Examples of haloalkyl groupsinclude fluoromethyl, chloromethyl, bromomethyl, and trifluoromethyl.

As used herein, the term “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, the term “ALK5 and/or ALK4 inhibitor” refers to acompound, other than inhibitory Smads, e.g. Smad6 and Smad7, whichselectively inhibits the ALK5 and/or ALK4 receptors preferentially overp38 or type II receptors.

As used herein, the term “ALK5- and/or ALK4-mediated disease state”refers to any disease state which is mediated (or modulated) by ALK5and/or ALK4, for example, a disease which is modulated by the inhibitionof the phosphorylation of Smad2 and Smad3 in the TGF-β and/or activinsignaling pathways.

As used herein, the term “ulcers” is used to include, but not to belimited to, diabetic ulcers, chronic ulcers, gastric ulcers, andduodenal ulcers.

Compounds of formula (I) may be prepared by a number of known methodsfrom commercially available or known starting materials. If the startingmaterials are unavailable from a commercial source, they can be preparedby procedures known in the art.

In one method, compounds of formula (I) wherein A₁ is N and A₂ is NH, orA₁ is NH and A₂ is N are prepared according to Scheme 1. Specifically,optionally substituted 2-methylpyridine (II) is deprotonated by a basesuch as n-BuLi, NaHMDS, LDA or LiHMDS before reacting with R₁COOR₈ (III)wherein R₈ is C₁₋₆alkyl, R₁COCl (IV), or R₁-substituted carboxylic acidmethoxy-methyl-amide (V) to form a ketone (VI). The methoxy-methyl-amide(V) can be prepared by reacting a corresponding acid chloride (IV) withN,O-dimethylhydroxylamine hydrochloride. The ketone (VI) may be oxidizedto a diketone (VII) with HBr in DMSO. This diketone (VII) can then becondensed with an appropriately substituted aldehyde (VIII) or protectedaldehyde derivative in the presence of ammonium acetate to yield acompound of formula (I). R₁, R₂, R₃, and X have been defined as above.The aldehyde (VIII) can be prepared according to the methods outlined inWO 02/096875 A1 and Liquid Crystals 10:273-287 (1991). Alternatively,the ketone (VI) can be treated with sodium nitrite in HCl or acetic acidto afford an (x-keto-oxime (IX), which can be then condensed with anappropriately substituted aldehyde (VIII) or protected aldehydederivative in the presence of ammonium acetate to give theN-hydroxyimidazoles. Treatment of this with triethylphophite affords acompound of formula (I).

The resulting compounds of this invention represented by the formula(I)-(IX) can be separated and purified by appropriate conventionalmethods such as column chromatography and recrystallization.

Compounds of the invention may be administered by any suitable route,for example by oral, buccal, sub-lingual, rectal, vaginal, nasal,topical or parenteral (including intravenous, intramuscular,subcutaneous and intracoronary) administration.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually, they will form up to about 80% of theformulation.

For administration to man in the curative or prophylactic treatment ofthe disorders identified above, oral, buccal or sub-lingual dosages of acompound of formula (I) will generally be in the range of from 50-5000mg daily for an average adult patient (70 kg). Thus for a typical adultpatient, individual tablets or capsules contain from 25-500 mg of activecompound, in a suitable pharmaceutically acceptable vehicle or carrier,for administration in single or multiple doses, once or several timesper day. Dosages for parenteral administration will typically be withinthe range of from 25-250 mg per single dose as required. In practice thephysician will determine the actual dosing regimen which will be mostsuitable for an individual patient and it will vary with the age, weightand response of the particular patient. The above dosages are exemplaryof the average case but there can be individual instances in whichhigher or lower dosage ranges may be merited, and such are within thescope of this invention.

For human use, a compound of formula (I) can be administered alone, butwill generally be administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example, the compound may beadministered orally, buccally or sublingually, in the form of tabletscontaining excipients such as starch or lactose, or in capsules orovules either alone or in admixture with excipients, or in the form ofelixirs or suspensions containing flavoring or coloring agents. Suchliquid preparations may be prepared with pharmaceutically acceptableadditives such as suspending agent (e.g. methylcellulose, asemi-synthetic glyceride such as witepsol or mixtures of glycerides suchas a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8and caprylic/capric glycerides). A compound may also be injectedparenterally, for example intravenously, intramuscularly, subcutaneouslyor intracoronarily. For parenteral administration, the compound is bestused in the form of a sterile aqueous solution which may contain othersubstances, for example, salts, or monosaccharides such as mannitol orglucose, to make the solution isotonic with blood.

Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, together with a pharmaceuticallyacceptable diluent or carrier therefor.

The invention also provides a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition containing either entity, for use in therapy.

The invention further provides the use of a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition containing either entity, for the manufactureof a medicament for the treatment of a disease, mediated by the ALK5and/or ALK4 receptors in mammals.

ALK5- and/or ALK4-mediated disease states include, but are not limitedto, glomerulonephritis, diabetic nephropathy, lupus nephritis,hypertension-induced nephropathy, renal interstitial fibrosis, renalfibrosis resulting from complications of drug exposure, HIV-associatednephropathy, transplant necropathy, liver fibrosis due to alletiologies, hepatic dysfunction attributable to infections,alcohol-induced hepatitis, disorders of the biliary tree, pulmonaryfibrosis, acute lung injury, adult respiratory distress syndrome,idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease,pulmonary fibrosis due to infectious or toxic agents, post-infarctioncardiac fibrosis, congestive heart failure, dilated cardiomyopathy,myocarditis, vascular stenosis, restenosis, atherosclerosis, ocularscarring, corneal scarring, proliferative vitreoretinopathy, excessiveor hypertrophic scar or keloid formation in the dermis occurring duringwound healing resulting from trauma or surgical wounds, peritoneal andsub-dermal adhesion, scleroderma, fibrosclerosis, progressive systemicsclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis,ulcers, impaired neurological function, male erectile dysfunction,Peyronie's disease, Dupuytren's contracture, Alzheimer's disease,Raynaud's syndrome, fibrotic cancers, tumor metastasis growth,radiation-induced fibrosis, and thrombosis.

The invention further provides a method of inhibiting the TGF-β and/oractivin signaling pathways in mammals, for example, inhibiting thephosphorylation of Smad2 or Smad3 by ALK5 and/or ALK4.

The invention further provides a method of reducing the accumulation ofexcess extracellular matrix in mammals by inhibiting the TGF-β and/oractivin signaling pathways, for example, inhibiting the phosphorylationof Smad2 or Smad3 by ALK5 and/or ALK4.

The invention further provides a method of inhibiting metastasis oftumor cells in mammals by inhibiting the TGF-β signaling pathway.

The invention further provides a method of treating carcinomas mediatedby an overexpression of TGF-β in mammals by inhibiting the TGF-βsignaling pathway.

The present invention is further illustrated in the following Examples,which should not be taken to limit the scope of the invention describedin the claims. In the Examples, electrospray ionization mass spectra(ESI-MS) were obtained on a LCQ DECA XP Plus mass spectrometer (ThermoFinnigan, USA).

EXAMPLES Practice Example 1 Preparation of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide(Example 79)

To a stirred solution of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile(Example 78, prepared according to the method described in US2008/0319012 A1) (130 mg, 0.31 mmol) in acetic acid (3 mL) was addedconc. H₂SO₄ (0.7 mL) and the mixture was stirred at 100° C. After 2hours, more conc. H₂SO₄ (0.2 mL) was added and the mixture was stirredat 100° C. for 1 hour. Then the reaction mixture was cooled to roomtemperature, diluted with H₂O (10 mL) in the ice bath, and neutralizedby addition of NH₄OH solution to pH 7. The mixture was extracted withCH₂Cl₂ (3 times) and then the organic layer was dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by MPLC (MeOH:CH₂Cl₂=1:20 (v/v) to 1:10 (v/v)) to afford thesolid, which was recrystallized from CH₂Cl₂/MeOH/Et₂O to give the titlecompound (131.6 mg, 68%). ¹H NMR (300 MHz, CD₃OD) δ 2.53 (3H, s), 4.23(2H, s), 7.16-7.23 (3H, m), 7.54-7.59 (2H, m), 7.84 (1H, dd), 8.04 (2H,bs), 8.25 (1H, bs), 8.85 (2H, dd). MS (ESI) m/z 439 (MH⁺).

Practice Example 2 Preparation of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol(Example 81)

A mixture of6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline(Example 80, prepared according to the method described in US2008/0319012 A1) (948 mg, 2.23 mmol) and pyridine hydrochloride (95 g)was stirred at 190° C. for 80 min. Then the hot reaction mixture waspoured into H₂O (60 mL) and added NH₄OH solution to pH 5. The aqueoussolution was extracted with CH₂Cl₂ (30 mL, 7 times) and then the organiclayer was dried over MgSO₄, filtered, and evaporated under reducedpressure. The residue was purified by MPLC (MeOH:CH₂Cl₂=1:30 (v/v) to1:15 (v/v)) to afford the solid, which was recrystallized fromCH₂Cl₂/Et₂O to give the title compound (635 mg, 69%). ¹H NMR (300 MHz,CDCl₃) δ 2.34 (3H, s), 3.95 (2H, s), 6.50 (1H, d), 6.56-6.57 (1H, m),6.79 (1H, dd), 6.91 (1H, d), 7.25-7.33 (2H, m), 7.78 (1H, m), 7.91-7.97(2H, m), 8.03 (1H, s), 8.81 (1H, d), 10.80 (1H, bs), 11.48 (1H, bs). MS(ESI) m/z 411 (MH⁺).

Practice Example 3 Preparation of6-(2-(4-fluoro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline(Example 87)

To a stirred solution of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol(Example 81) (80 mg, 0.195 mmol) in acetone (6 mL) and DMF (3 mL) wereadded 1-(2-chloroethyl)pyrrolidine hydrochloride (50 mg, 0.292 mmol) andK₂CO₃ (81 mg, 0.585 mmol). The mixture was stirred at 60° C. for 6hours, cooled to room temperature, and diluted with H₂O (10 mL). Themixture was extracted with CH₂Cl₂ (25 mL, 3 times), and then the organiclayer was dried over Na₂SO₄, filtered, and evaporated under reducedpressure. The residue was purified by MPLC on NH silica gel(MeOH:CH₂Cl₂=1:50 (v/v) to 1:20 (v/v)) to afford the title compound(52.7 mg, 53%). ¹H NMR (300 MHz, CDCl₃) δ 1.78 (4H, pentet), 2.51 (3H,s), 2.63 (4, td), 2.93 (2H, t), 4.16 (2H, s), 7.18 (2H, t), 6.85-6.90(1H, m), 6.94-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd),7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.01 (1H, bs). MS(ESI) m/z 508 (MH⁺).

Practice Example 4 Preparation of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline(Example 73)

To a stirred solution of6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline(Example 72, prepared according to the method described in US2008/0319012 A1) (448 mg, 1.02 mmol) in MeOH (30 mL) were added ammoniumformate (257 mg, 4.08 mmol) and 10% Pd/C (30 mg) and the mixture wasstirred at room temperature for 100 min. The reaction mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure. The residue was diluted with H₂O (50 mL) and added 2N HClsolution until all remaining substances were dissolved. The aqueoussolution was neutralized by addition of NH₄OH solution to pH 7. Theprecipitate was filtered, washed with H₂O, and dried under vacuum. Theprecipitate was purified by MPLC (MeOH:CH₂Cl₂=1:20 (v/v) to 1:15 (v/v))to afford the title compound (445.5 mg, 80%). ¹H NMR (300 MHz, CDCl₃) δ2.50 (3H, s), 4.10 (2H, s), 6.64-6.72 (2H, m), 6.92 (1H, d), 6.95 (1H,d), 7.24 (1H, s), 7.35-7.39 (1H, m), 7.41 (1H, dd), 7.96 (1H, dd), 8.10(1H, d), 8.14-8.17 (2H, m), 8.91 (1H, dd). MS (ESI) m/z 410 (MH⁺).

Practice Example 5 Preparation of2-chloro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline(Example 75)

To a suspension of6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline(Example 74, prepared according to the method described in US2008/0319012 A1) (50 mg, 0.110 mmol) in MeOH (2 mL) was added SnCl₂ (104mg, 0.548 mmol) and the mixture was stirred at 55° C. After 2.5 hours,the reaction mixture was cooled to room temperature, concentrated underreduced pressure. The residue was diluted with H₂O (5 mL), filtered, andthe filtrate was washed with 2N HCl (5 mL) and neutralized by additionof 5N NaOH solution to pH 7˜8. The precipitate was filtered, washed withH₂O and Et₂O, and dried under vacuum for overnight. The precipitate waspurified by MPLC on silica gel (MeOH:EA:CH₂Cl₂=1:20:80 (v/v) to 1:4:16(v/v)), and on NH silica gel (MC) to afford the title compound (33.1 mg,71%). ¹H NMR (300 MHz, CDCl₃) δ 2.50 (3H, s), 4.09 (2H, s), 6.66 (1H,dd), 6.68 (1H, s), 6.96 (1H, d), 7.19 (1H, d), 7.25 (1H, bs), 7.36-7.39(1H, m), 7.40 (1H, dd), 7.96 (1H, d), 8.10 (1H, d), 8.15-8.16 (2H, m),8.91 (1H, dd). MS (ESI) m/z 426 (MH⁺).

Practice Example 6 Preparation of2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenylamino)ethanol(Example 90)

To a suspension of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline(Example 73) (100 mg, 0.244 mmol) in toluene (450 uL) and DMF (0.2 mL)were added 2-bromoethanol (21 uL, 0.293 mmol), N,N-diisopropylethylamine(300 uL, 1.72 mmol) and the mixture was stirred at 70° C. After 5 hours,additional 2-bromoethanol (5 uL) was added, and stirred at 100° C. forovernight. The reaction mixture was cooled to room temperature, dilutedwith H₂O (4 mL), and extracted with CH₂Cl₂ (2 mL, 3 times). The organiclayer was dried over Na₂SO₄, filtered, and evaporated under reducedpressure. The residue was purified by MPLC on NH silica gel(MeOH:CH₂Cl₂=1:50 (v/v)) to afford the title compound (38 mg, 34%). ¹HNMR (300 MHz, CDCl₃) δ 2.49 (3H, s), 3.31 (2H, bs), 3.83 (2H, t), 4.10(2H, s), 6.56-6.60 (1H, m), 6.76 (1H, d), 6.87-6.96 (2H, m), 7.22 (1H,d), 7.34-7.42 (2H, m), 7.93 (1H, d), 8.09 (1H, d), 8.15 (2H, bs), 8.90(1H, dd), 10.45 (1H, bs). MS (ESI) m/z 454 (MH⁺).

Practice Example 7 Preparation of2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine(Example 96)

To a stirred solution of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol(Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were addedtert-butyl 2-bromoethylcarbamate (109 mg, 0.488 mmol) and K₂CO₃ (67 mg,0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. Thereaction mixture was cooled to room temperature, diluted with H₂O (20mL), and extracted with CH₂Cl₂ (5 mL, 3 times). The organic layer wasdried over Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by MPLC on NH silica gel (MeOH:CH₂Cl₂=1:50 (v/v))to give tert-butyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethylcarbamate(123.5 mg, 91%). This compound was dissolved in CH₂Cl₂ (5 mL), andp-anisole (224 uL, 2.23 mmol) and trifluoroacetic acid (1 mL) wereadded. The mixture was stirred for 1 hour, then concentrated, dilutedwith H₂O (10 mL), and neutralized by addition of aqueous NH₄OH solutionto pH 7˜8. The aqueous solution was saturated with NH₄Cl solid,extracted with CH₂Cl₂ (5 mL, 3 times), and then the organic layer wasdried over Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by MPLC on NH silica gel (MeOH:CH₂Cl₂=3:100 (v/v))to afford the title compound (70.2 mg, 69%). ¹H NMR (300 MHz, CDCl₃) δ2.50 (3H, s), 3.09 (2H, t), 4.04 (2H, t), 4.16 (2H, s), 6.85-6.90 (1H,m), 6.95-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97(1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.40 (1H, bs). MS (ESI) m/z454 (MH⁺).

Practice Example 8 Preparation of methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate(Example 93)

To a stirred solution of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol(Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added methyl3-chloropropanoate (32 uL, 0.366 mmol) and K₂CO₃ (67 mg, 0.488 mmol) andthe mixture was stirred at 60° C. for 20 hours. The reaction mixture wascooled to room temperature, diluted with H₂O (20 mL), and extracted withCH₂Cl₂ (5 mL, 3 times). The organic layer was dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by MPLC on NH silica gel (MeOH:CH₂Cl₂=1:50 (v/v)) to afford thetitle compound (88.4 mg, 75%). (300 MHz, CDCl₃) δ 2.50 (3H, s), 3.74(3H, s), 4.16 (2H, s), 4.71 (2H, s), 6.91-6.97 (3H, m), 7.06 (1H, td),7.24 (1H, s), 7.37 (1H, d), 7.42 (1H, dd), 7.97 (1H, d), 8.10-8.18 (3H,m), 8.92 (1H, dd), 10.35 (1H, bs). MS (ESI) m/z 483 (MH⁺).

Practice Example 9 Preparation of2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide(Example 97)

Methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate(Example 93) (32.5 mg, 0.067 mmol) was treated with aqueous NH₄OH(28-30%, 1 mL). The suspension was stirred at room temperature. After 2hours, the reaction mixture was diluted with H₂O (3 mL) and stirred for30 min. The precipitate was filtered, washed with water, and dried undervacuum for overnight to afford the title compound (26.8 mg, 86%). (300MHz, CDCl₃) δ 2.49 (3H, s), 4.15 (2H, s), 4.51 (2H, s), 5.80 (N—H, 1H,bs), 6.71 (N—H, 1H, bs), 6.63-7.06 (4H, m), 7.25-7.28 (1H, m), 7.37-7.44(2H, m), 7.94 (1H, dd), 8.10 (1H, d), 8.16-8.18 (2H, m), 8.91 (1H, dd),11.00 (1H, bs). MS (ESI) m/z 468 (MH⁺).

Practice Example 10 Preparation of2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)aceticacid (Example 98)

To a stirred solution of methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate(Example 93) (47.5 mg, 0.098 mmol) was added aqueous NaOH solution (6mg, 0.148 mmol, H₂O (0.3 mL)). The reaction mixture was stirred for 1hour, then diluted H₂O (3 mL), and neutralized by addition of aceticacid to pH 7. The precipitate was filtered, washed with water, and driedunder vacuum for overnight to afford the title compound (42.6 mg, 93%).(300 MHz, CDCl₃+CD₃OD) δ 2.57 (3H, s), 4.04 (N—H, 1H, bs), 4.75 (N—H,1H, bs), 6.86 (1H, bs), 7.11 (2H, d), 7.23 (1H, d), 7.46-7.53 (2H, m),7.85 (1H, dd), 8.05 (1H, d), 8.20 (1H, bs), 8.25 (1H, d), 8.87 (1H, dd).MS (EST) m/z 469 (MH⁺).

Practice Example 11 Preparation of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoicacid (Example 104)

2-Fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile(Example 76) (300 mg, 0.715 mmol) was treated with conc. H₂SO₄ (2.4 mL)and H₂O (0.8 ml) and the mixture was stirred at 120° C. for 10 hours.The reaction mixture was cooled to room temperature and basified to pH9-10 with 5N NaOH solution in the ice bath. The solution was extractedwith CH₂Cl₂ (5 mL, 3 times), and then the aqueous layer was acidified topH 4 with 2N HCl solution. The precipitate was filtered, washed withH₂O, and dried under vacuum for overnight to afford the title compound(213 mg, 49%). (300 MHz, CDCl₃+CD₃OD) δ 2.48 (3H, s), 4.15 (2H, s), 6.97(1H, d), 7.05 (1H, dd), 7.14 (1H, d), 7.35-7.42 (2H, m), 7.47-7.52 (1H,m), 7.83 (1H, dd), 7.90 (1H, dd), 8.01 (1H, d), 8.08 (1H, d), 8.16 (1H,dd), 8.80 (1H, dd). MS (ESI) m/z 439 (MH⁺).

Practice Example 12 Preparation of6-(2-(4-fluoro-3-(1H-tetrazol-5-yl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline(Example 105)

A mixture of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile(Example 76) (100 mg, 0.238 mmol) and sodium azide (20.9 mg, 0.321 mmol)in toluene (1 mL) was stirred at 120° C. for overnight. The reactionmixture was cooled to room temperature and basified to pH 9-10 with 5NNaOH solution in the ice bath. The mixture was extracted with CH₂Cl₂ (5mL, 3 times), and then the aqueous layer was acidified to pH 4 with 2NHCl solution. The precipitate was filtered, washed with H₂O, and driedunder vacuum for overnight to afford the solid, which was recrystallizedfrom MeOH/CH₂Cl₂/Et₂O to give the title compound (56 mg, 51%). (300 MHz,CDCl₃+CD₃OD) δ 2.49 (3H, s), 4.17 (2H, s), 6.98 (1H, d), 7.08 (1H, dd),7.13 (1H, d), 7.35-7.41 (2H, m), 7.45-7.50 (1H, m), 7.81 (1H, dd),7.97-8.01 (2H, m), 8.05 (1H, d), 8.13 (1H, dd), 8.80 (1H, dd). MS (ESI)m/z 463 (MH⁺).

Practice Example 13 Preparation of2-fluoro-N-(2-hydroxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide(Example 107)

A mixture of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoicacid (Example 104) (50 mg, 0.114 mmol), HOBt (23 mg, 0.171 mmol), DMAP(3 mg, 0.023 mmol), and 2-aminoethanol in pyridine (1 mL) was added EDC(33 mg, 0.171 mmol) and the mixture was stirred at room temperature for4 hours. The reaction mixture was poured into H₂O and extracted withCH₂Cl₂ (5 mL, 3 times). The organic layer was dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by MPLC (MeOH:CH₂Cl₂=1:100 (v/v) to 1:20 (v/v)) to afford thetitle compound (34.7 mg, 61%). (300 MHz, CDCl₃) δ 2.37 (3H, s), 3.57(2H, q), 3.79 (2H, t), 4.15 (2H, s), 6.91 (1H, dd), 6.96 (1H, d),7.04-7.15 (1H, m), 7.20-7.30 (1H, m), 7.37-7.43 (2H, m), 7.80 (1H, dd),7.85 (1H, dd), 8.04 (1H, d), 8.10 (1H, d), 8.14 (1H, dd), 8.90 (1H, dd),MS (ESI) m/z 482 (MH⁺).

Practice Example 14 Preparation of(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanamine(Example 108)

To a suspension of2-Fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile(Example 76) (100 mg, 0.238 mmol) in THF (1.5 mL) was added LAH (1Msolution in THF, 476 uL, 0.476 mmol) and the mixture was stirred at roomtemperature for 2 hours. The reaction was quenched by addition of ethylacetate (1 mL) and H₂O (3 drops), and the mixture was stirred for 30min. The mixture was dried over Na₂SO₄, filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by MPLC (MeOH:CH₂Cl₂=1:50 (v/v) to 1:20 (v/v)) to afford thetitle compound (53.2 mg, 53%). (300 MHz, CDCl₃+CD₃OD) δ 2.49 (3H, s),3.87 (2H, s), 4.17 (2H, s), 6.95-7.01 (2H, m), 7.17-7.33 (3H, m),7.35-7.43 (2H, m), 7.96 (1H, d), 8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40(1H, bs), MS (ESI) m/z 424 (MH⁺).

Practice Example 15 Preparation of(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanol(Example 109)

To a suspension of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoicacid (Example 104) (75 mg, 0.171 mmol) in THF (1 mL) was added LAH (1Msolution in THF, 342 uL, 0.342 mmol) and the mixture was stirred at roomtemperature for 2 hours. The reaction was quenched by addition of ethylacetate (1 mL) and H₂O (3 drops), and the mixture was stirred for 30min. The mixture was dried over Na₂SO₄, filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by MPLC (MeOH:CH₂Cl₂=1:50 (v/v) to 1:20 (v/v)) to afford thetitle compound (16.9 mg, 23%). (300 MHz, CDCl₃) δ 2.50 (3H, s), 4.09(2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H,t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH⁺).

Practice Example 16 Preparation of6-(5-(6-methylpyridin-2-yl)-2-(3-(pyrrolidin-1-yl)benzyl)-1H-imidazol-4-yl)quinoline(Example 110)

To a solution of6-(5-(6-methylpyridin-2-yl)-2-(3-nitrobenzyl)-1H-imidazol-4-yl)quinoline(500 mg, 1.186 mmol, prepared according to the method described in US2008/0319012 A1) in MeOH (5 mL) was added Pd/C (0.5 mg, 10% w/w) and themixture was stirred under H₂ at atmospheric pressure for 5 hours. Thereaction mixture was filtered through celite and the filterate wasconcentrated under reduced pressure. The residue was purified by MPLC onsilica gel (MeOH:CH₂Cl₂=1:50) to afford the3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline(424 mg, 91%). The obtained compound,3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline(30 mg, 0.077 mmol) was dissolved in DMF (3 mL), treated with1,4-dibromobutane (17 mg, 0.080 mmol), and stirred at 120° C. for 12hours. The reaction mixture was cooled to room temperature, added H₂O(30 mL), and extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by MPLC (MeOH:CH₂Cl₂=1:20 (v/v)) and on NH silicagel (MeOH:CH₂Cl₂=1:100 (v/v)) to afford the title compound (7 mg,20.5%). (300 MHz, CDCl₃) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H,m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41(1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH⁺).

Practice Example 17 Preparation of2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline(Example 112)

To a stirred solution of6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline(49.6 mg, 0.113 mmol, prepared according to the method described in US2008/0319012 A1) in MeOH (5 mL) were added Raney Ni (0.1 mg, 10% w/w)and hydrazine monohydrate (0.027 mL, 0.563 mmol) and the mixture wasstirred at room temperature for overnight. The reaction mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure. The residue was purified by MPLC (MeOH:CH₂Cl₂=1:50 (v/v)) andon NH silica gel (MeOH:CH₂Cl₂=1:100 (v/v)) to afford the title compound(37.8 mg, 82%). (300 MHz, CDCl₃) δ 1.99 (4H, m), 2.54 (3H, s), 3.23 (4H,t), 4.31 (2H, s), 6.37 (1H, dd), 6364 (1H, d), 6.95 (1H, d), 7.23-7.43(5H, m), 7.98 (1H, dd), 8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40 (1H, bs)MS (ESI) m/z 446 (MH⁺).

The compounds listed in the following Table 1 were prepared in ananalogous manner to those described in US 2008/0319012 A1 and thePractice Examples 1-17 above. The ¹H NMR and mass spectral data of thesecompounds are included in the Table 1.

TABLE 1 Mass data (m/z) Example Structure ¹H NMR (MH⁺) 1

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.27 (2H, s), 6.96 (1H, d), 7.29 (1H,bs), 7.36-7.47 (3H, m), 7.52 (1H, s), 7.54 (1H, s), 7.63 (1H, s), 7.97(1H, dd), 8.11 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd) 445 2

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.20 (2H, s), 6.91-6.96 (2H, m), 7.05(1H, dd), 7.10 (1H, d), 7.24-7.32 (2H, m), 7.37 (1H, d), 7.41 (1H, dt),7.97 (1H, dd), 7.97 (1H, dd), 8.10-8.19 (3H, m), 8.92 (1H, dd) 395 3

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.18 (2H, s), 6.96 (1H, d), 7.20 (1H,d), 7.28 (2H, bs), 7.37-7.43 (3H, m), 7.50 (1H, bs), 7.97 (1H, dd),8.10-8.18 (3H, m), 8.92 (1H, dd) 456 4

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.19 (2H, s), 6.96 (1H, d), 7.20-7.28(4H, m), 7.34 (1H, bs), 7.39 (1H, d), 7.42 (1H, t), 7.98 (1H, dd),8.10-8.19 (3H, m), 8.92 (1H, dd) 411 5

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.06 (3H, s), 4.30 (2H, s), 6.97 (1H,d), 7.29 (1H, s), 7.37-7.44 (2H, m), 7.53 (1H, t), 7.65 (1H, d), 7.84(1H, dt), 7.95 (1H, bs), 7.98 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd)455 6

(300 MHz, CDCl₃) δ 4.28 (2H, s), 7.28 (1H, bs), 7.36 (1H, t), 7.44 (1H,dd), 7.46 (1H, d), 7.49 (1H, s), 7.54-7.56 (2H, m), 7.63 (1H, s), 7.92(1H, dd), 8.12-8.19 (3H, m), 8.93 (1H, dd) 510 7

(300 MHz, CDCl₃) δ 4.22 (2H, s), 6.98 (1H, td), 7.07 (1H, dt), 7.12 (1H,d), 7.25- 7.28 (1H, m), 7.31 (2H, dd), 7.41 (1H, d), 7.43 (1H, d), 7.93(1H, dd), 8.12-8.19 (3H, m), 8.93 (1H, dd) 460 8

(300 MHz, CDCl₃) δ 4.15 (2H, s), 7.19 (1H, t), 7.24 (1H, td), 7.25-7.32(3H, m), 7.31 (2H, dd), 7.34 (1H, s), 7.37 (1H, td), 7.43 (1H, dd), 7.50(1H, t), 7.87 (1H, dd), 8.08 (1H, dd), 8.14 (1H, d), 8.21 (1H, dd), 8.86(1H, dd) 521 9

(300 MHz, CDCl₃) δ 4.21 (2H, s), 7.23- 7.30 (4H, m), 7.34 (2H, td), 7.41(1H, bs), 7.45 (1H, dd), 7.93 (1H, dd), 8.13-8.21 (3H, m), 8.94 (1H, dd)476 10

(300 MHz, CDCl₃) δ 2.48 (3H, s), 2.77 (3H, s), 4.27 (2H, s), 6.95 (1H,d), 7.29-7.37 (3H, m), 7.46 (1H, d), 7.53 (2H, bs), 7.63 (1H, s), 7.92(1H, dd), 8.01-8.07 (2H, m), 8.11 (1H, s) 459 11

(300 MHz, CDCl₃) δ 2.48 (3H, s), 2.77 (3H, s), 4.18 (2H, s), 6.94 (1H,d), 7.20 (1H, t), 7.24-7.31 (3H, m), 7.35 (1H, d), 7.40 (1H, td), 7.51(1H, bs), 7.92 (1H, dd), 8.04 (2H, dt), 8.12 (1H, d) 470 12

(300 MHz, CDCl₃) δ 2.48 (3H, s), 2.77 (3H, s), 4.18 (2H, s), 6.94 (1H,d), 7.21-7.39 (7H, m), 7.93 (1H, dd), 8.04 (2H, dt), 8.12 (1H, d) 425 13

(300 MHz, CDCl₃) δ 2.48 (3H, s), 2.77 (3H, s), 4.21 (2H, s), 6.93-6.99(2H, m), 7.06 (1H, dt), 7.15 (1H, dt), 7.24-7.29 (2H, m), 7.31 (1H, s),7.35 (1H, d), 7.92 (1H, dd), 8.05 (2H, t), 8.12 (1H, d) 409 14

(300 MHz, CDCl₃) δ 2.52 (3H, s), 5.77 (3H, s), 3.07 (3H, s), 4.31 (2H,s), 6.96 (1H, d), 7.25-7.32 (2H, m), 7.37 (1H, t), 7.55 (1H, t), 7.68(1H, dt), 7.85 (1H, dt), 7.92 (1H, dd), 7.96 (1H, bs), 8.01-8.07 (2H,m), 8.10 (1H, m) 469 15

(300 MHz, CDCl₃) δ 2.77 (3H, s), 4.28 (2H, s), 7.24 (1H, d), 7.27-7.34(1H, m), 7.39 (1H, bs), 7.48 (1H, dt), 7.50 (1H, d), 7.54 (2H, bs), 7.56(1H, d), 7.64 (1H, s), 7.88 (1H, dd), 8.04 (1H, d), 8.08 (1H, d), 8.11(1H, s) 524 16

(300 MHz, CDCl₃) δ 2.77 (3H, s), 4.18 (2H, s), 7.19-7.33 (5H, m), 7.41(2H, td), 7.50 (1H, s), 7.88 (1H, dd), 8.03-8.07 (2H, m), 8.10 (1H, s)535 17

(300 MHz, CDCl₃) δ 2.70 (3H, s), 4.10 (2H, s), 7.19-7.23 (4H, m), 7.27(1H, s), 7.29- 7.31 (3H, m), 7.79 (1H, dd), 7.96 (1H, d), 8.04-8.05 (1H,m), 8.07 (1H, s) 490 18

(300 MHz, CDCl₃) δ 2.77 (3H, s), 4.21 (2H, s), 6.98 (1H, td), 7.07 (1H,dt), 7.13 (1H, d), 7.24 (1H, d), 7.26-7.37 (4H, m), 7.88 (1H, dd), 8.03(1H, d), 8.06 (1H, d), 8.10 (1H, s) 474 19

(300 MHz, CDCl₃) δ 2.57 (3H, s), 3.90 (3H, s), 6.93-7.00 (3H, m), 7.33(1H, bs), 7.39- 7.45 (2H, m), 7.55-7.65 (5H, m) 424 20

(300 MHz, CDCl₃) δ 2.49 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.92-6.99(3H, m), 7.22- 7.28 (3H, m), 7.33 (2H, d), 7.39 (1H, d), 7.59 (2H, dt)390 21

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.22 (2H, s), 6.95 (1H, d), 7.23 (1H,s), 7.36-7.44 (4H, m), 7.48-7.52 (2H, m), 7.57-7.60 (3H, m) 428 22

(300 MHz, CDCl₃) δ 2.44 (3H, s), 4.14 (2H, s), 6.92-6.97 (2H, m), 7.01(1H, dt), 7.06 (1H, d), 7.23-7.31 (2H, m), 7.36- 7.43 (3H, m), 7.58 (1H,s), 7.61 (1H, s) 378 23

(300 MHz, CDCl₃) δ 2.46 (3H, s), 4.21 (2H, s), 6.00 (2H, s), 6.85 (1H,d), 6.92 (1H, s), 7.10 (2H, bs), 7.31 (1H, d), 7.41 (1H, t), 7.42 (1H,t), 7.50-7.52 (2H, m), 7.60 (1H, s) 438 24

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.12 (2H, s), 6.00 (2H, s), 6.86 (1H,d), 6.92 (1H, s), 7.12-7.25 (4H, m), 7.30 (1H, s), 7.33 (1H, s), 7.41(1H, t) 404 25

(300 MHz, CDCl₃) δ 2.43 (3H, s), 4.14 (2H, s), 6.00 (2H, s), 6.85 (1H,dd), 6.91 (1H, d), 6.93 (1H, td), 7.01 (1H, dt), 7.06 (1H, d), 7.10 (1H,s), 7.12 (1H, dd), 7.22-7.27 (2H, m), 7.30 (1H, d), 7.40 (1H, t) 388 26

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.26 (2H, s), 6.97 (1H, d), 7.34 (1H,d), 7.42 (2H, m), 7.50 (1H, s), 7.53 (1H, s), 7.62 (1H, s), 8.14 (2H,s), 8.41 (1H, s), 8.84 (2H, dd) 446 27

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.19 (2H, s), 6.98 (1H, d), 7.20-7.25(3H, m), 7.34- 7.44 (3H, m), 8.13 (1H, s), 8.14 (1H, s), 8.41 (1H, s),8.84 (1H, d), 8.85 (1H, d) 412 28

(300 MHz, CDCl₃) δ 2.43 (3H, s), 4.19 (2H, s), 6.91 (1H, dd), 6.96 (1H,d), 7.03 (1H, dt), 7.08 (1H, d), 7.23-7.44 (3H, m), 8.14 (2H, bs), 8.42(1H, s), 8.84 (2H, dd) 396 29

(300 MHz, CDCl₃) δ 4.28 (2H, s), 7.12 (1H, dd), 7.37 (1H, bs), 7.42 (1H,d), 7.45 (1H, d), 7.52 (1H, d), 7.55 (1H, s), 7.58 (1H, s), 7.64 (1H,s), 7.93 (1H, dd), 8.13 (1H, s), 8.16 (1H, d), 8.20 (1H, d), 8.94 (1H,dd) 465 30

(300 MHz, CDCl₃) δ 4.18 (2H, s), 7.09 (1H, dd), 7.23-7.27 (4H, m), 7.33(1H, bs), 7.40 (1H, d), 7.42 (1H, d) 7.91 (1H, dd), 8.10-8.17 (3H, m),8.92 (1H, dd) 432 31

(300 MHz, CDCl₃) δ 2.53 (3H, s), 4.22 (2H, s), 7.01 (1H, d), 7.25-7.32(4H, m), 7.38 (1H, s), 7.41-7.46 (2H, m), 8.03 (1H, d), 8.05 (1H, s),8.15 (1H, d), 8.21 (1H, s) 446 32

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.24 (2H, s), 6.94 (1H, d), 7.06-7.13(2H, m), 7.21- 7.27 (2H, m), 7.34-7.42 (3H, m), 7.96 (1H, dd), 8.08 (1H,s) 8.13 (1H, d), 8.17 (1H, s), 8.91 (1H, dd) 395 33

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.19 (2H, s), 6.98 (1H, d), 7.00-7.05(2H, m), 7.24- 7.35 (3H, m), 7.38 (1H, s), 7.41 (1H, dd), 7.97 (1H, dd),8.09 (1H, s), 8.14 (1H, d), 8.18 (1H, s), 8.92 (1H, dd) 395 34

(300 MHz, CDCl₃) δ 2.56 (3H, s), 4.17 (2H, s), 6.99 (1H, dd), 7.04 (1H,d), 7.20 (1H, bs), 7.27 (1H, dt), 7.43 (1H, bs), 7.47 (1H, dd), 7.89(1H, dd), 8.06 (1H, d), 8.12 (1H, d), 8.23 (1H, d), 8.85 (1H, dd) 431 35

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.25 (2H, s), 6.97 (1H, d), 7.08-7.15(2H, m), 7.23- 7.32 (2H, m), 7.37-7.43 (2H, m), 8.12 (2H, s), 8.04 (1H,s), 8.91 (2H, dd), 10.16 (1H, bs) 396 36

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.19 (2H, s), 6.97 (1H, d), 6.99-7.05(2H, m), 7.29- 7.34 (3H, m), 7.38-7.43 (1H, m), 8.14 (2H, s), 8.41 (1H,s), 8.84 (2H, dd), 10.16 (1H, bs) 396 37

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.17 (2H, s), 6.92-7.00 (2H, m),7.20-7.29 (1H, m), 7.29-7.34 (1H, m), 7.39-7.44 (1H, m), 8.13 (2H, bs),8.41 (1H, s), 8.85 (2H, dd) 432 38

(300 MHz, CDCl₃) δ 2.55 (3H, s), 4.15 (2H, s), 7.03 (1H, d), 7.11-7.16(2H, m), 7.20- 7.26 (2H, m), 7.42 (1H, d), 7.46 (1H, dd), 7.89 (1H, dd),8.06 (1H, d), 8.13 (1H, d), 8.22 (1H, dd), 8.85 (1H, dd) 413 39

(300 MHz, CDCl₃) δ 2.56 (3H, s), 4.15 (2H, s), 7.03 (1H, d), 7.10 (1H,t), 7.19 (1H, bs), 7.30-7.35 (1H, m), 7.39-7.41 (1H, m), 7.46 (1H, dd),7.60 (1H, dd), 7.90 (1H, dd), 8.06 (1H, d), 8.13 (1H, dd), 8.23 (1H, d),8.86 (1H, dd) 474 40

(300 MHz, CDCl₃) δ 2.51 (3H, s), 4.42 (2H, s), 6.95 (1H, d), 7.25-7.27(1H, m), 7.35- 7.39 (2H, m), 7.42 (1H, dd), 7.48-7.55 (2H, m), 7.71 (1H,d), 7.97 (1H, dd), 8.11 (1H, d), 8.16-8.17 (2H, m), 8.92 (1H, m) 445 41

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.26 (2H, s), 6.96 (1H, d), 7.28 (1H,s), 7.36-7.42 (2H, m), 7.44 (1H, s), 7.46 (1H, s), 7.56 (1H, s), 7.59(1H, s), 7.97 (1H, dd), 8.10 (s, 1H), 8.14 (1H, d), 8.18 (1H, s), 8.92(1H, dd) 445 42

(300 MHz, CDCl₃) δ 2.56 (3H, s), 4.32 (2H, s), 7.04 (1H, d), 7.21 (1H,bs), 7.41-7.48 (2H, m), 7.79 (H, s), 7.88-7.90 (1H, m), 7.92 (2H, s),8.06 (1H, d), 8.13 (1H, dd), 8.22 (1H, d), 8.86 (1H, dd) 513 43

(300 MHz, CDCl₃ + CD₃OD) δ 2.54 (3H, s), 4.17 (2H, s), 7.02 (1H, d),7.19 (1H, bs), 7.31-7.34 (4H, m), 7.39-7.42 (1H, m), 7.46 (1H, dd), 7.89(1H, dd), 8.06 (1H, d), 8.13 (1H, d), 8.22 (1H, d), 8.85 (1H, dd) 411 44

(300 MHz, CDCl3) δ 2.47 (3H, s), 4.18 (2H, s), 6.69 (1H, tt), 6.83-6.90(2H, m), 6.97 (1H, d), 7.29 (1H, s), 7.38-7.44 (2H, m), 7.97 (1H, dd),8.11-8.19 (3H, m), 8.93 (1H, dd), 10.27 (1H, bs) 413 45

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.26 (2H, s), 6.96 (1H, d), 7.02-7.15(3H, m), 7.24 (1H, s), 7.37 (1H, d), 7.41 (1H, dd), 7.96 (1H, dd), 8.11(1H, d), 8.15-8.17 (2H, m), 8.92 (1H, dd), 10.25 (1H, bs) 413 46

(300 MHz, CDCl₃) δ 2.46 (3H, s), 4.21 (2H, s) 6.98 (1H, d), 7.14 (1H,t), 7.29 (1H, s), 7.38-7.44 (2H, m), 7.49-7.53 (1H, m), 7.59 (1H, dd),7.96 (1H, dd), 8.12 (1H, d), 8.17 (2H, bs), 8.92 (1H, dd), 10.28 (1H,bs) 463 47

(300 MHz, CDCl₃) δ 2.47 (3H, s), 3.85 (3H, s), 4.14 (2H, s), 6.87-6.97(2H, m), 7.02 (1H, d), 7.08 (1H, d), 7.25-7.27 (1H, m), 7.36- 7.43 (2H,m), 7.96 (1H, dd), 8.11 (1H, d), 8.16-8.18 (2H, m), 8.92 (1H, dd), 10.22(1H, bs) 425 48

(300 MHz, CDCl₃) δ 2.47 (3H, s), 3.85 (3H, s), 4.13 (2H, s), 6.85 (1H,d), 6.96 (1H, d), 7.17 (1H, dd), 7.27 (1H, m), 7.35 (1H, m), 7.44 (2H,m), 7.96 (1H, dd), 8.11 (1H, d), 8.16-8.18 (2H, m), 8.92 (1H, dd) 441 49

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.21 (2H, s), 6.96 (1H, d), 7.16 (1H,s), 7.19 (1H, d), 7.28 (1H, s), 7.35-7.44 (4H, m), 7.96 (1H, dd), 8.11(1H, d), 8.16-8.18 (2H, m), 8.92 (1H, dd), 10.20 (1H, bs) 461 50

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.27 (2H, s), 6.98 (1H, d). 7.03-7.10(2H, m), 7.13- 7.18 (1H, m), 7.32 (1H, d), 7.41 (1H, t), 8.12 (2H, s),8.40 (1H, s), 8.84 (2H, dd), 10.23 (1H, bs) 414 51

(300 MHz, CDCl₃) δ 2.55 (3H, s), 4.16 (2H, s), 7.05 (1H, d), 7.11-7.16(2H, m), 7.23- 7.27 (2H, m), 7.44 (1H, bs), 8.07 (2H, bs), 8.33 (1H, s),8.84 (2H, s) 414 52

(300 MHz, CDCl₃) δ 2.50 (3H, s), 4.19 (2H, s), 6.70 (1H, tt), 6.85-6.91(2H, m), 6.99 (1H, d), 7.33-7.36 (1H, m), 7.40-7.45 (1H, d), 8.14 (2H,s), 8.42 (1H, s), 8.85 (2H, dd), 10.23 (1H, bs) 414 53

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.29 (2H, s), 6.99 (1H, d), 7.21 (1H,t), 7.33 (1H, d), 7.42 (1H, t), 7.52 (1H, td), 7.62 (1H, td), 8.11-8.12(2H, m), 8.40 (1H, d), 8.84 (2H, dd), 10.27 (1H, bs) 464 54

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.22 (2H, s), 6.99 (1H, d), 7.16 (1H,t), 7.34 (1H, d), 7.42 (1H, t), 7.51-7.56 (1H, m), 7.61 (1H, dd),8.12-8.14 (2H, m), 8.41 (1H, s), 8.85 (2H, dd), 10.22 (1H, bs) 464 55

(300 MHz, CDCl₃) δ 2.51 (3H, s), 4.42 (2H, s), 6.97 (1H, d), 7.30-7.42(3H, m), 7.49- 7.57 (2H, m), 7.71 (1H, d), 8.13 (2H, s), 8.43 (1H, s),8.84 (2H, dd), 10.08 (1H, bs) 446 56

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.25 (2H, s), 6.97 (1H, d), 7.32-7.39(2H, m), 7.44 (2H, d), 7.57 (2H, d), 8.14 (2H, s), 8.41 (1H, s), 8.84(2H, dd), 10.28 (1H, bs) 446 57

(300 MHz, CDCl₃) δ 2.53 (3H, s), 4.34 (2H, s), 6.99 (1H, d), 7.33-7.44(2H, m), 7.81 (1H, s), 7.87 (2H, s), 8.10-8.18 (2H, m), 8.42 (1H, s),8.85 (2H, dd), 10.08 (1H, bs) 514 58

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.15 (2H, s), 6.98 (1H, d), 7.06 (1H,t), 7.22-7.25 (1H, m), 7.33-7.35 (1H, m), 7.40-7.45 (1H, m), 7.54 (1H,dd), 8.14 (2H, s), 8.41 (1H, s), 8.84 (2H, dd), 10.25 (1H, bs) 475 59

(300 MHz, CDCl₃) δ 2.46 (3H, s), 3.84 (3H, s), 4.13 (2H, s), 6.89 (1H,t), 6.98-7.03 (2H, m), 7.08 (1H, dd), 7.31-7.34 (1H, m), 7.38- 7.43 (1H,m), 8.14 (2H, s), 8.42 (1H s), 8.84 (2H, dd), 10.24 (1H, bs) 426 60

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.18 (2H, s), 6.97 (1H, d), 7.28-7.33(4H, m), 7.38- 7.43 (1H, m), 8.14 (2H, s), 8.41 (1H, s), 8.84 (2H, dd),10.12 (1H, bs) 412 61

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.36 (2H, s), 6.98 (1H, d), 7.16 (1H,t), 7.28-7.33 (2H, m), 7.36-7.43 (2H, m), 8.12 (2H, s), 8.41 (1H, s),8.84 (2H, dd), 10.28 (1H, bs) 447 62

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.15 (2H, s), 6.99 (1H, d), 7.16 (1H,dd), 7.33- 7.45 (4H, m), 8.14 (2H, s), 8.84 (2H, dd), 10.23 (1H, bs) 44763

(300 MHz, CDCl₃) δ 2.51 (3H, s), 4.30 (2H, s), 6.98 (1H, d), 7.21 (1H,dd), 7.26- 7.36 (2H, m), 7.41-7.44 (2H, m), 8.12 (2H, s), 8.39 (1H, s),8.84 (2H, dd) 447 64

(300 MHz, CDCl₃) δ 2.48 (3H, s), 3.87 (3H, s), 4.13 (2H, s), 6.88 (1H,d), 6.97 (1H, d), 7.19 (1H, dd), 7.32 (1H, d), 7.37 (1H, d), 7.42 (1H,d), 8.14 (2H, s), 8.42 (1H, s), 8.84 (2H, dd), 10.16 (1H, bs) 442 65

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.21 (2H, s), 6.98 (1H, d), 7.16 (1H,s), 7.19 (qH, d), 7.33-7.42 (4H, m), 8.14 (2H, d), 8.41 (1H, s), 8.84(2H, dd), 10.20 (1H, bs) 462 66

(300 MHz, CDCl₃) δ 2.48 (3H, s), 3.86 (3H, s), 4.13 (2H, s), 6.84 (1H,d), 6.97 (1H, d), 7.23 (1H, dd), 7.31-7.33 (1H, m), 7.38- 7.43 (1H, m),7.54 (1H, d), 8.14 (2H, s), 8.42 (1H, s), 8.84 (2H, dd), 10.20 (1H, bs)487 67

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.20 (2H, s), 6.92 (1H, dd), 6.97 (1H,d), 7.00- 7.05 (3H, m), 7.08-7.13 (2H, m), 7.29- 7.42 (5H, m), 8.13 (2H,s), 8.41 (1H, s), 8.84 (2H, dd), 10.04 (1H, bs) 470 68

(300 MHz, CDCl₃) δ 2.47 (3H, s), 4.27 (2H, s), 6.97 (1H, d), 7.18 (1H,t), 7.25-7.28 (1H, m), 7.37-7.44 (2H, m), 7.50 (1H, t), 7.58 (1H, t),7.95 (1H, dd), 8.09-8.17 (3H, m), 8.92 (1H, dd), 10.83 (1H, bs) 463 69

(300 MHz, CDCl₃ + CD₃OD) δ 2.54 (3H, s), 4.30 (2H, s), 7.01 (1H, d),7.19-7.22 (1H, m), 7.24 (1H, dd), 7.34-7.48 (4H, m), 7.91 (1H, dd), 8.08(1H, d), 8.13 (1H, d), 8.22 (1H, d), 8.87 (1H, dd) 446 70

(300 MHz, CDCl₃) δ 2.48 (3H, s), 3.85 (3H, s), 4.13 (2H, s), 6.84 (1H,d), 6.96 (1H, d), 7.23 (1H, dd), 7.24-7.28 (1H, m), 7.36- 7.44 (2H, m),7.53 (1H, d), 7.98 (1H, dd), 8.11 (1H, d), 8.16-8.18 (2H, m), 8.92 (1H,dd), 10.38 (1H, bs) 486 71

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.13 (2H, s), 6.00 (2H, s), 6.84-6.87(1H, m), 6.91- 7.01 (2H, m), 7.09 (1H, s), 7.11 (1H, dd), 7.14-7.23 (1H,m), 7.31 (1H, d), 7.42 (1H, t) 424 72

(300 MHz, CD₃OD) δ 2.53 (3H, s), 4.08 (2H, s), 6.41 (1H, d), 6.42 (1H,bs), 6.61 (1H, dd), 6.84 (1H, bs), 6.94-6.99 (1H, m), 7.18- 7.28 (3H,m), 7.36 (1H, dd), 7.46 (1H, s), 8.06 (2H, dd) 440 73

(300 MHz, CDCl₃) δ 2.50 (3H, s), 4.10 (2H, s), 6.64-6.72 (2H, m), 6.92(1H, d), 6.95 (1H, d), 7.24 (1H, s), 7.35-7.39 (1H, m), 7.41 (1H, dd),7.96 (1H, dd), 8.10 (1H, d), 8.14- 8.17 (2H, m), 8.91 (1H, dd) 410 74

(300 MHz, CDCl₃) δ 2.55 (3H, s), 4.25 (2H, s), 7.01 (1H, d), 7.21 (1H,bs), 7.40 (1H, bs), 7.44 (1H, dd), 7.52 (1H, d), 7.59 (1H, dd), 7.91(1H, d), 7.93 (1H, d), 8.09 (1H, d), 8.13 (1H, d), 8.20 (1H, d), 8.88(1H, dd) 456 75

(300 MHz, CDCl₃) δ 2.50 (3H, s), 4.09 (2H, s), 6.66 (1H, dd), 6.68 (1H,s), 6.96 (1H, d), 7.19 (1H, d), 7.25 (1H, bs), 7.36-7.39 (1H, m), 7.40(1H, dd), 7.96 (1H, d), 8.10 (1H, d), 8.15-8.16 (2H, m), 8.91 (1H, dd)426 76

(300 MHz, CDCl₃ + CD₃OD) δ 2.52 (3H, s), 4.16 (2H, s), 6.98 (1H, d),7.13-7.19 (2H, m), 7.35 (1H, d), 7.41 (1H, dd), 7.60-7.64 (2H, m), 7.86(1H, dd), 8.04 (1H, d), 8.08 (1H, d), 8.17 (1H, d), 8.83 (1H, dd) 420 77

(300 MHz, DMSO-d₆) δ 2.51 (3H, s), 4.21 (2H, s), 7.15-7.22 (3H, m),7.52- 7.59 (3H, m), 7.84 (1H, dd), 7.88 (1H, s), 7.99 (1H, s), 8.12 (1H,d), 8.32 (1H, d), 8.82 (1H, dd) 438 78

(300 MHz, CDCl₃) δ 2.51 (3H, s), 4.20 (2H, s), 7.01 (1H, d), 7.17 (1H,t), 7.34-7.46 (2H, m), 7.57-7.62 (2H, m), 8.10-8.17 (2H, m), 8.40 (1H,s), 8.85 (2H, dd) 421 79

(300 MHz, CD₃OD) δ 2.53 (3H, s), 4.23 (2H, s), 7.16-7.23 (3H, m),7.54-7.59 (2H, m), 7.84 (1H, dd), 8.04 (2H, bs), 8.25 (1H, bs), 8.85(2H, dd) 439 80

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.89 (3H, s), 4.18 (2H, s), 6.85-6.90(1H, m),6.95- 7.08 (3H, m), 7.25-7.28 (1H, m), 7.36- 7.44 (2H, m), 7.97(1H, dd), 8.10 (1H, s), 8.13-8.18 (2H, m), 8.92 (1H, dd), 10.05 (1H, bs)425 81

(300 MHz, CDCl₃) δ 2.34 (3H, s), 3.95 (2H, s), 6.50 (1H, d), 6.56-6.57(1H, m), 6.79 (1H, dd), 6.91 (1H, d), 7.25-7.33 (2H, m), 7.78 (1H, m),7.91-7.97 (2H, m), 8.03 (1H, s), 8.81 (1H, d), 10.80 (1H, bs), 11.48(1H, bs) 411 82

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.19 (2H, s), 6.98 (1H, d), 7.25-7.30(2H, m), 7.37- 7.45 (2H, m), 7.68 (1H, dd), 7.97 (1H, dd), 8.11-8.19(3H, m), 8.40 (1H, d), 8.93 (1H, dd) 412 83

(300 MHz, CDCl₃) δ 2.45 (3H, s), 4.21 (2H, s), 6.96 (1H, d), 7.22-7.27(2H, m), 7.36- 7.44 (2H, m), 7.66 (1H, dt), 7.98 (1H, dd), 8.10-8.19(3H, m), 8.50 (1H, dd), 8.60 (1H, dd), 8.92 (1H, dd), 11.40 (1H, bs) 37884

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.24 (2H, s), 6.97 (1H, d), 7.14 (1H,d), 7.24-7.29 (3H, m), 7.33-7.44 (3H, m), 7.98 (1H, d), 8.12 (1H, d),8.16-8.18 (2H, m), 8.92 (1H, dd), 10.11 (1H, bs) 461 85

(300 MHz, CDCl₃) δ 2.50 (3H, s), 4.25 (2H, s), 6.99 (1H, d), 7.14 (1H,d), 7.24-7.28 (1H, m), 7.32-7.43 (4H, m), 8.14 (2H, s), 8.41 (1H, s),8.85 (2H, dd) 462 86

(300 MHz, CDCl₃) δ 2.33 (6H, s), 2.52 (3H, s), 2.75 (2H, t), 4.14 (2H,t), 4.18 (2H, s), 6.87-6.92 (1H, m), 6.95-7.08 (3H, m), 7.24 (1H, s),7.35-7.44 (2H, m), 7.98 (1H, dd), 8.10-8.18 (3H, m), 8.92 (1H, dd), 9.85(1H, bs) 482 87

(300 MHz, CDCl₃) δ 1.78 (4H, pentet), 2.51 (3H, s), 2.63 (4, td), 2.93(2H, t), 4.16 (2H, s), 7.18 (2H, t), 6.85-6.90 (1H, m), 6.94-7.07 (3H,m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18(3H, m), 8.92 (1H, dd), 10.01 (1H, bs) 508 88

(300 MHz, CDCl₃) δ 2.51 (3H, s), 2.57 (4H, t), 2.81 (2H, t), 3.70 (4H,t), 4.16 (2H, t), 4.17 (2H, s), 6.86-6.91 (1H, m), 6.95- 7.08 (3H, m),7.24 (1H, s), 7.36 (1H, d), 7.42 (1H, dd), 7.97 (1H, dd), 8.10-8.18 (3H,m), 8.92 (1H, dd), 9.98 (1H, bs) 524 89

(300 MHz, CDCl₃) δ 2.00 (2H, pentet), 2.24 (6H, s), 2.47 (2H, t), 2.50(3H, s), 4.09 (2H, t), 4.16 (2H, s), 6.84-6.88 (1H, m), 6.95-7.07 (3H,m), 7.24 (1H, s), 7.35- 7.44 (2H, m), 7.97 (1H, dd), 8.10-8.18 (3H, m),8.92 (1H, dd) 496 90

(300 MHz, CDCl₃) δ 2.49 (3H, s), 3.31 (2H, bs), 3.83 (2H, t), 4.10 (2H,s), 6.56-6.60 (1H, m), 6.76 (1H, d), 6.87-6.96 (2H, m), 7.22 (1H, d),7.34-7.42 (2H, m), 7.93 (1H, d), 8.09 (1H, d), 8.15 (2H, bs), 8.90 (1H,dd), 10.45 (1H, bs) 454 91

(300 MHz, CDCl₃) δ 2.46 (3H, s), 3.90 (2H, t), 4.10 (2H, t), 4.12 (2H,s), 6.81-6.86 (1H, m), 6.93-7.00 (3H, m), 7.24 (1H, s), 7.67- 7.43 (2H,m), 7.94 (1H, dd), 8.10 (1H, d), 8.16 (2H, bs), 8.91 (1H, dd), 10.88(1H, bs) 455 92

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.43 (3H, s), 3.75 (2H, t), 4.16 (2H,s), 4.18 (2H, t), 6.86-6.91 (1H, m), 6.94-7.08 (3H, m), 7.24 (1H, s),7.36 (1H, s), 7.42 (1H, dd), 7.98 (1H, dd), 8.11 (1H, d), 8.16-8.18 (2H,m), 8.92 (1H, dd), 10.22 (1H, bs) 469 93

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.74 (3H, s), 4.16 (2H, s), 4.71 (2H,s), 6.91-6.97 (3H, m), 7.06 (1H, td), 7.24 (1H, s), 7.37 (1H, d), 7.42(1H, dd), 7.97 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd), 10.35 (1H, bs)483 94

(300 MHz, CDCl₃) δ 2.40 (3H, s), 3.91 (2H, t), 4.09 (2H, t), 4.11 (2H,s), 6.78-6.83 (1H, m), 6.91-6.99 (3H, m), 7.34 (1H, d), 7.43 (1H, t),8.15 (2H, s), 8.38 (1H, s), 8.84 (2H, s), 11.25 (1H, bs) 456 95

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.43 (3H, s), 3.76 (2H, t), 4.16 (2H,s), 4.18 (2H, t), 6.87-6.91 (1H, m), 6.96-7.08 (3H, m), 7.31 (1H, d),7.40 (1H, t), 8.14 (2H, s), 8.42 (1H, s), 8.84 (2H, dd), 10.30 (1H, bs)470 96

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.09 (2H, t), 4.04 (2H, t), 4.16 (2H,s), 6.85-6.90 (1H, m), 6.95-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d),7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.40(1H, bs) 454 97

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.15 (2H, s), 4.51 (2H, s), 5.80 (N −H, 1H, bs), 6.71 (N − H, 1H, bs), 6.63-7.06 (4H, m), 7.25- 7.28 (1H, m),7.37-7.44 (2H, m), 7.94 (1H, dd), 8.10 (1H, d), 8.16-8.18 (2H, m), 8.91(1H, dd), 11.00 (1H, bs) 468 98

(300 MHz, CDCl₃ + CD₃OD) δ 2.57 (3H, s), 4.04 (N − H, 1H, bs), 4.75 (N −H, 1H, bs), 6.86 (1H, bs), 7.11 (2H, d), 7.23 (1H, d), 7.46-7.53 (2H,m), 7.85 (1H, dd), 8.05 (1H, d), 8.20 (1H, bs), 8.25 (1H, d), 8.87 (1H,dd) 469 99

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.09 (2H, t), 4.05 (2H, t), 4.16 (2H,s), 6.85-6.90 (1H, m), 6.95-7.07 (3H, m), 7.30 (1H, d), 7.40 (1H, t),8.13 (2H, s), 8.41 (1H, s), 8.84 (2H, dd) 455 100

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.77 (3H, s), 4.16 (2H, s), 4.71 (2H,s), 6.92-6.99 (3H, m), 7.04-7.10 (1H, m), 7.33 (1H, d), 7.41 (1H, t),8.13 (2H, s), 8.40 (1H, s), 8.84 (2H, dd) 484 101

(300 MHz, CDCl₃ + CD₃OD) δ 2.48 (3H, s), 4.05 (2H, s), 4.63 (2H, s),6.84-6.89 (1H, m), 6.93-7.04 (3H, m), 7.22 (1H, d), 7.45 (1H, t), 7.94(1H, dd), 8.01 (1H, d), 8.22 (1H, d), 8.76 (2H, dd) 470 102

(300 MHz, CDCl₃) δ 2.49 (3H, s), 4.15 (2H, s), 4.52 (2H, s), 5.82 (N −H, 1H, bs), 6.76 (N − H, 1H, bs), 6.93-7.07 (4H, m), 7.33 (1H, d), 7.42(1H, t), 8.13 (2H, s), 8.38 (1H, s), 8.84 (2H, dd) 469 103

(300 MHz, CDCl₃) δ 2.59 (3H, s), 4.37 (2H, s), 6.98 (1H, d), 7.25-7.28(2H, m), 7.32 (1H, d), 7.37-7.44 (2H, m), 7.64 (1H, t), 7.97 (1H, dd),8.11 (1H, d), 8.15-8.18 (2H, m), 8.92 (1H, dd), 11.05 (1H, bs) 412 104

(300 MHz, CDCl₃ + CD₃OD) δ 2.48 (3H, s), 4.15 (2H, s), 6.97 (1H, d),7.05 (1H, dd), 7.14 (1H, d), 7.35-7.42 (2H, m), 7.47- 7.52 (1H, m), 7.83(1H, dd), 7.90 (1H, dd), 8.01 (1H, d), 8.08 (1H, d), 8.16 (1H, dd), 8.80(1H, dd) 439 105

(300 MHz, CDCl₃ + CD₃OD) δ 2.49 (3H, s), 4.17 (2H, s), 6.98 (1H, d),7.08 (1H, dd), 7.13 (1H, d), 7.35-7.41 (2H, m), 7.45- 7.50 (1H, m), 7.81(1H, dd), 7.97-8.01 (2H, m), 8.05 (1H, d), 8.13 (1H, dd), 8.80 (1H, dd)463 106

(300 MHz, CDCl₃) δ 2.50 (3H, s), 3.39 (3H, s), 3.56 (2H, q), 3.67 (2H,dt), 4.23 (2H, s), 6.95 (1H, d), 7.08 (1H, dd), 7.23 (1H, s), 7.35-7.49(3H, m), 7.96 (1H, dd), 8.06- 8.11 (2H, m), 8.16-8.18 (2H, m), 8.92 (1H,dd), 10.70 (1H, bs) 496 107

(300 MHz, CDCl₃) δ 2.37 (3H, s), 3.57 (2H, q), 3.79 (2H, t), 4.15 (2H,s), 6.91 (1H, dd), 6.96 (1H, d), 7.04-7.15 (1H, m), 7.20- 7.30 (1H, m),7.37-7.43 (2H, m), 7.80 (1H, dd), 7.85 (1H, dd), 8.04 (1H, d), 8.10 (1H,d), 8.14 (1H, dd), 8.90 (1H, dd) 482 108

(300 MHz, CDCl₃ + CD₃OD) δ 2.49 (3H, s), 3.87 (2H, s), 4.17 (2H, s),6.95-7.01 (2H, m), 7.17-7.33 (3H, m), 7.35-7.43 (2H, m), 7.96 (1H, d),8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40 (1H, bs) 424 109

(300 MHz, CDCl₃) δ 2.42 (3H, s), 4.08 (2H, s), 4.58 (2H, s), 6.89 (1H,dd), 6.97 (1H, d), 7.13-7.18 (1H, m), 7.22-7.26 (2H, m), 7.38- 7.43 (2H,m), 7.93 (1H, dd), 8.08 (1H, d), 8.13-8.15 (2H, m), 8.91 (1H, dd), 11.20(1H, bs) 425 110

(300 MHz, CDCl₃) δ 1.99 (4H, m), 2.54 (3H, s), 3.23 (4H, t), 4.31 (2H,s), 6.37 (1H, dd), 6364 (1H, d), 6.95 (1H, d), 7.23-7.43 (5H, m), 7.98(1H, dd), 8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40 (1H, bs) 446 111

(300 MHz, CDCl₃) δ 2.52 (3H, s), 4.27 (2H, s), 7.19 (1H, d), 7.39 (1H,dd), 7.58- 7.64 (1H, m), 7.72-7.77 (1H, m), 8.04 (2H, bs), 8.14 (1H,dd), 8.24 (1H, s), 8.84 (2H, dd) 441 112

(300 MHz, CDCl₃) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m),6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H,s), 8.84 (2H, dd) 411 113

(300 MHz, CDCl₃) δ 2.57 (3H, s), 4.40 (2H, s), 6.97 (1H, d), 7.19-7.26(2H, m), 7.35- 7.42 (3H, m), 7.67 (1H, td), 7.96 (1H, dd), 8.08 (1H, d),8.14-8.16 (2H, m), 8.65 (1H, d), 8.90 (1H, dd), 11.00 (1H, bs) 378 114

(300 MHz, CDCl₃) δ 2.48 (3H, s), 4.16 (2H, s), 6.96 (1H, d), 7.15-7.26(3H, m), 7.36- 7.50 (4H, m), 7.96 (1H, dd), 8.11 (1H, d), 8.17 (2H, m),8.92 (1H, dd), 10.40 (1H, br s) 456 115

(300 MHz, CDCl₃) δ 4.18 (2H, s), 7.07- 7.11 (1H, m), 7.23 (2H, m),7.40-7.51 (5H, m), 7.97 (1H, dd), 8.12-8.19 (3H, m), 8.48 (1H, m), 8.93(1H, dd) 442 116

(300 MHz, CDCl₃) δ 3.91 (3H, s), 4.20 (2H, s), 6.57 (1H, d), 7.05 (1H,d), 7.26 (2H, m), 7.36-7.44 (2H, m), 7.51 (2H, m), 7.99 (1H, dd),8.11-8.18 (3H, m), 8.92 (1H, dd) 472The chemical names of the compounds listed in the Table 1 are asfollows:

-   -   1.        6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   2.        6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   3.        6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   4.        6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   5.        6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline    -   6.        6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   7.        6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)quinoline    -   8.        6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   9.        6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)quinoline    -   10.        2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   11.        6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline    -   12.        6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline    -   13.        6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline    -   14.        2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline    -   15.        6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-2-methylquinoline    -   16.        6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline    -   17.        6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline    -   18.        6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline    -   19.        2-(4-(4-methoxyphenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   20.        2-(2-(3-chlorobenzyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-6-methylpyridine    -   21.        2-(4-(4-chlorophenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   22.        2-(4-(4-chlorophenyl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   23.        2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   24.        2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-chlorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   25.        2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   26.        6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline    -   27.        6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   28.        6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   29.        6-(5-(6-chloropyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   30.        6-(2-(3-chlorobenzyl)-5-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   31.        2-chloro-6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   32.        6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   33.        6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   34.        6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoline    -   35.        6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   36.        6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   37.        6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoxaline    -   38.        6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   39.        6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   40.        6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   41.        6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline    -   42.        6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   43.        6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   44.        6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   45.        6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   46.        6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   47.        6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-H-imidazol-4-yl)quinoline    -   48.        6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   49.        6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoline    -   50.        6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   51.        6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   52.        6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   53.        6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   54.        6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   55.        6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline    -   56.        6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline    -   57.        6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   58.        6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   59.        6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   60.        6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   61.        6-(2-(2,3-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   62.        6-(2-(3,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   63.        6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   64.        6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   65.        6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoxaline    -   66.        6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   67.        6-(5-(6-methylpyridin-2-yl)-2-(3-phenoxybenzyl)-1H-imidazol-4-yl)quinoxaline    -   68.        6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   69.        6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   70.        6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   71.        2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine    -   72.        6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   73.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline    -   74.        6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   75.        2-chloro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline    -   76.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile    -   77.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide    -   78.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile    -   79.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide    -   80.        6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   81.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol    -   82.        6-(2-((6-chloropyridin-3-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   83.        6-(5-(6-methylpyridin-2-yl)-2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)quinoline    -   84.        6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoline    -   85.        6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethoxy)benzyl)-1H-imidazol-4-yl)quinoxaline    -   86.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylethanamine    -   87.        6-(2-(4-fluoro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   88.        4-(2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethyl)morpholine    -   89.        3-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylpropan-1-amine    -   90.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenylamino)ethanol    -   91.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol    -   92.        6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   93. Methyl        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate    -   94.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol    -   95.        6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   96.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine    -   97.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide    -   98.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetic        acid    -   99.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine    -   100. methyl        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate    -   101.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetic        acid    -   102.        2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide    -   103.        6-(2-((6-chloropyridin-2-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   104.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoic        acid    -   105.        6-(2-(4-fluoro-3-(1H-tetrazol-5-yl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   106.        2-fluoro-N-(2-methoxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide    -   107.        2-fluoro-N-(2-hydroxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide    -   108.        (2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanamine    -   109.        (2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanol    -   110.        6-(5-(6-methylpyridin-2-yl)-2-(3-(pyrrolidin-1-yl)benzyl)-1H-imidazol-4-yl)quinoline    -   111.        6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline    -   112.        2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline    -   113.        6-(5-(6-methylpyridin-2-yl)-2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)quinoline    -   114.        6-(2-(4-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   115.        6-(2-(4-bromobenzyl)-5-(pyridin-2-yl)-1H-imidazol-4-yl)quinoline    -   116.        6-(2-(4-bromobenzyl)-5-(6-methoxypyridin-2-yl)-1H-imidazol-4-yl)quinoline

Biological Data

The biological activity of the compounds of the invention may beassessed using the following assays:

Cell-Free Assay for Evaluating Inhibition of ALK5 Kinase Phosphorylationof Smad3

The His-tagged, constitutively active ALK5 (T204D) and Smad3 fullprotein were expressed in insect cells using the Invitrogen BacNBluebaculovirus expression system. Expressed proteins were purified withQiagen Ni-NTA resin column. The purified smad3 protein 200 ng was mixedwith 100 μL of 0.1 M sodium bicarbonate coating buffer and coated intoFlash-Plates by pipetting. Plates were covered and incubated at 4° C.for 16 hours. Then the plates were washed 3 times with 200 μL of coatingbuffer and allowed to block in 1% BSA in PBS at room temperature for 1hour. The purified ALK5 protein 100 ng was mixed with 100 μL of reactionbuffer containing 20 mM Tris-HCl (pH 7.4), 5 mM MgCl₂, 1 mM CaCl₂, 1 mMDTT, 1 μM ATP and 2 μCi γ-³²p-ATP, and 1 μL of each test compound offormula (I) prepared in 100% DMSO solution at different concentrations.The assay was then initiated with the addition of ALK5 reaction mixtureinto Smad3-coated Flash-Plates, followed by incubation at 30° C. for 3hours. After incubation, the assay buffer was removed and washed 3 timeswith 200 μL of 10 mM sodium pyrophosphate solution. Then, theFlash-Plates were air-dried and counted on a Packard TopCount.

Compounds of formula (I) typically exhibited IC₅₀ values of less than 10μM; some exhibited IC₅₀ values of less than 1 μM; and some evenexhibited IC₅₀ values less than 50 nM.

Cell-Free Assay for Evaluating Inhibition of ALK4 Kinase Phosphorylationof Smad3

Inhibition of the ALK4 kinase phosphorylation of Smad3 by test compoundsof formula (□) can be determined in a similar manner to that describedabove for ALK5 inhibition except that a similarly His-tagged ALK4 isused in place of the His-tagged, constitutively active ALK5.

Compounds of formula (□) typically exhibited IC₅₀ values of less than 10μM; some exhibited IC₅₀ values of less than 1 μM.

Assay for Evaluating Cellular Inhibition of TGF-β Signaling

Biological activity of the compounds of formula (□) was determined bymeasuring their ability to inhibit TGF-β1-induced Smad bindingelement-luciferase (SBE-Luc) reporter activity and PAI-1-luciferase(p3TP-Lux) reporter activity in HepG2 cells. HepG2 cells weretransiently transfected with either SBE-Luc reporter construct orp3TP-Lux reporter construct grown in DMEM medium containing 10% FBS,penicillin 100 U/mL, streptomycin 100 μg/mL, L-glutamine 2 mM, sodiumpyruvate 1 mM, and non-essential amino acids. The transfected cells werethen plated at a concentration of 2.5×10⁴ cells/well in 96 well platesand starved for 3-6 hours in media with 0.5% FBS at 37□ in a 5% CO₂incubator. The cells were then stimulated with 5 ng/mL TGF-β1 ligand inthe starvation media containing 1% DMSO either in the presence orabsence of a test compound of formula (□) and incubated at 37□ in a 5%CO₂ incubator for 24 hours. The media was washed out, and the luciferaseactivity in cell lysates was determined by using a luciferase assaysystem (Promega).

Compounds of formula (□) typically exhibited IC₅₀ values of less than 10μM; some exhibited IC₅₀ values of less than 1 μM; and some evenexhibited IC₅₀ values of less than 50 μM.

FIG. 1 shows effect of the compounds of Examples 32, 45, 73, 79, and 83on TGF-β1-induced 3TP-Luc reporter activity in HepG2 cells.

What is claimed is:
 1. A compound of formula (I):

wherein R₁ is naphthyl, anthracenyl, or phenyl optionally substitutedwith substituents selected from halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,C₁₋₆alkyl, C₁₋₆haloalkyl, —O— (CH₂)_(n)-Ph, —S— (CH₂)_(n)-Ph, cyano,phenyl, and CO₂R, wherein R is H or C₁₋₆alkyl, and n is 0, 1, 2, or 3;or R₁ is phenyl or pyridyl fused with an aromatic or non-aromatic cyclicring of 5-7 members wherein said cyclic ring optionally contains up tothree heteroatoms, independently selected from N, O and S, and the fusedphenyl or pyridyl may be further optionally substituted by halo, OH,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, cyano, phenyl or═O; R₂ is H, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl, phenyl,C₁₋₆haloalkyl, NH₂, NH(CH₂)_(n)-Ph, NH—C₁₋₆alkyl, halo, CN, NO₂, CONHRor SO₂NHR, wherein R is H or C₁₋₆alkyl, and n is 0, 1, 2, or 3;

R₃ is or R₃ is a heteroaromatic cyclic ring optionally substituted withsubstituents selected from halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,C₁₋₆alkyl, C₁₋₆haloalkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, —O—(CH₂)_(n)-Ph, —S— (CH₂)_(n)-Ph, cyano, phenyl, and CO₂R, wherein R is Hor C₁₋₆alkyl, and n is 0, 1, 2, or 3; or R₃ is phenyl fused with anaromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclicring optionally contains up to three heteroatoms, independently selectedfrom N, O and S, and the fused phenyl may be further optionallysubstituted by halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl,C₁₋₆haloalkyl, cyano, or phenyl; R₄ is halo, C₁₋₆haloalkyl, or—SO₂C₁₋₆alkyl; R₅ and R₆ are independently H, halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, —(CH₂)_(p)—NO₂, —(CH₂)_(p)—NR₇R₈, —(CH₂)_(p)—CHO,—(CH₂)_(p)—CONHOH, —(CH₂)_(p)—CN, —(CH₂)_(p)—CO₂H, (CH₂)_(p)—CO₂R₇,—CH₂)_(p)—CONR₇R₈, —(CH₂)_(p)—C(═NR₇)NR₇R₈, —(CH₂)_(p)-tetrazole,—(CH₂)_(p)—COR₇, —(CH₂)_(q)—(OR₉)₂, —(CH₂)_(p)—OR₇, —(CH₂)_(p)—CH═CH—CN,—(CH₂)_(p)—CH═CH—CO₂H, —(CH₂)_(p)—CH═CH—CO₂R₇, —(CH₂)_(p)—CH═CH—CONR₇R₈,—(CH₂)_(p)—NHCOR₇, —(CH₂)_(p)—NHCO₂R₇, —(CH₂)_(p)—CONHSO₂R₇,—(CH₂)_(p)—NHSO₂R₇ or —(CH₂)_(p)—CH═CH-tetrazole; R₇ and R₈ areindependently H, phenyl or C₁₋₆alkyl wherein phenyl or C₁₋₆alkyl isoptionally substituted by —(CH₂)_(q)—CONHOH, —(CH₂)_(q)—CN,—CH₂)_(q)—CO₂R₁₀, —(CH₂)_(q)—CONR₁₁R₁₂, —(CH₂)_(q)-tetrazole,—(CH₂)_(r)—OR₁₀, —(CH₂)_(r)—R₁₃, —(CH₂)_(r)—NR₁₁R₁₂; or R₇ and R₈ aretaken together to form a non-aromatic cyclic ring of 3-6 members whereinsaid cyclic ring optionally contains up to three heteroatoms,independently selected from N, O and S; R₉ is H or C₁₋₆alkyl; R₁₀, R₁₁and R₁₂ are independently H or C₁₋₆alkyl; R₁₃ is H or a 3-7 memberedheterocyclic ring optionally substituted at one, two or three positionsby halo, OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, cyano, oxo, carboxy or nitro;p is 0, 1, 2, 3, or 4; q is 1, 2, 3, or 4; r is 2, 3, or 4; X isC₁₋₁₀alkylene, C₂₋₁₀alkenylene or C₂₋₁₀alkynylene; one of A₁ and A₂ is Nand the other is NR₁₄; and R₁₄ is H, OH, C₁₋₆alkyl, or C₃₋₇cycloalkyl;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, which is selected from the group consisting of:6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)quinoline,2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazo-4-yl)-2-methylquinoline,2-(4-(4-methoxyphenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(2-(3-chlorobenzyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(4-chlorophenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(4-chlorophenyl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-chlorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-chloropyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chlorobenzyl)-5-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-chloro-6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoline,6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2,3-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline,6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-chloro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol,6-(2-((6-chloropyridin-3-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)quinoline,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylethanamine,3-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylpropan-1-amine,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenylamino)ethanol,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol,6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,Methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol,6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)-methyl)phenoxy)ethanamine,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)aceticacid,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-IH-imidazol-2-yl)methyl)phenoxy)ethanamine,Methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)aceticacid,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-IH-imidazol-2-yl)methyl)phenoxy)acetamide,6-(2-((6-chloropyridin-2-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoicacid,6-(2-(4-fluoro-3-(1H-tetrazol-5-yl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-N-(2-methoxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,2-fluoro-N-(2-hydroxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-IH-imidazol-2-yl)methyl)benzamide,(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanamine,(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanol,6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-quinoxaline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline,6-(5-(6-methylpyridin-2-yl)-2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(pyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(6-methoxypyridin-2-yl)-1H-imidazol-4-yl)quinoline;or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising one or more compounds according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.
 4. The pharmaceutical compositionaccording to claim 3, wherein said one or more compounds are selectedfrom the group consisting of:6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)quinoline,2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,2-methyl-6-(5-(6-methylpyridin-2-yl)-2-(3-(methylsulfonyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-2-methylquinoline,6-(2-(3-bromobenzyl)-5-(6-bromopyridin-2-yl)-1H-imidazol-4-yl)-2-methylquinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-chlorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline,6-(5-(6-bromopyridin-2-yl)-2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-methylquinoline,2-(4-(4-methoxyphenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(2-(3-chlorobenzyl)-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(4-chlorophenyl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(4-chlorophenyl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-chlorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,6-(5-(6-methylpyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-chloropyridin-2-yl)-2-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chlorobenzyl)-5-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-chloro-6-(2-(3-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoline,6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)-benzyl)-1H-imidazol-4-yl)quinoline,6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,3-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,5-difluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(2-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(5-(6-methylpyridin-2-yl)-2-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,5-bis(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-bromo-4-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-fluoro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(4-chlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2,3-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-chloro-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,6-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(2,4-dichlorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(3-bromo-4-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-(4-(benzo[d][1,3]dioxol-5-yl)-2-(2,4,5-trifluorobenzyl)-1H-imidazol-5-yl)-6-methylpyridine,6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline,6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-chloro-5-((−5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol,6-(2-((6-chloropyridin-3-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(5-(6-methylpyridin-2-yl)-2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)quinoline,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylethanamine,4-(2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethyl)morpholine,3-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)-N,N-dimethylpropan-1-amine,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenylamino)ethanol,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol,6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanol,6-(2-(4-fluoro-3-(2-methoxyethoxy)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-l)methyl)phenoxy)acetamide,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)aceticacid,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethanamine,methyl2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)aceticacid,2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetamide,6-(2-((6-chloropyridin-2-yl)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoicacid,6-(2-(4-fluoro-3-(1H-tetrazol-5-yl)benzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,2-fluoro-N-(2-methoxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,2-fluoro-N-(2-hydroxyethyl)-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide,(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanamine,(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanol,6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-quinoxaline,2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline,6-(5-(6-methylpyridin-2-yl)-2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(pyridin-2-yl)-1H-imidazol-4-yl)quinoline,6-(2-(4-bromobenzyl)-5-(6-methoxypyridin-2-yl)-1H-imidazol-4-yl)quinoline;or a pharmaceutically acceptable salt thereof.